bluuebunny/crossref_metadata_2025 huggingface dataset:
Practical approaches to early stage life sciences technology valuations
Authors: Mayhew Stephen
Published: January 2017

With fierce competition in the market for late stage life sciences assets, pharmaceutical companies seeking partnering strategies to bolster pipelines and drive long-term revenues are increasingly looking towards earlier stage compounds and technologies. Valuations are essential components of effective partnering transactions in the life sciences industry, however owing to the perceived uncertainty and risk associated with early stage life sciences technology, early stage valuations are a contentious area of valuation practice. Meaningful early stage valuations require new approaches that integrate complementary evaluation practices to build more widely accepted, balanced and transparent valuation outputs that facilitate productive and mutually beneficial transactions and form the basis for successful long-term partnerships. This article outlines a series of practical steps that encourage the use of encompassing approaches that blend complementary qualitative and quantitative techniques to build realistic and widely accepted early stage valuations. The methodology promotes rigorous interrogation of early stage life sciences technology to identify and characterise key value drivers, and advocates the development and simulation of robust practical scenarios to generate meaningful valuation outputs with practical relevance.
Biotechnology in the capital region of Europe
Authors: Wauters Jan
Published: January 2017

It has never been as challenging in biotechnology as today. Convergence is the key word, forcing alliances between pharmaceuticals and biology, and new economic opportunities arise from the growing interface between biotechnology and nanotechnology, nanobio. The challenges to bring such disruptive technologies to the market are unprecedented, ranging from truly multidisciplinary research to matching totally different business models among the various industries. In Flanders, Belgium, the message has been understood already 20 years ago.
Commentary regarding decision in Myriad Genetics on â€˜isolatedâ€™ DNA claims
Authors: Kowalski Thomas J , Lu Deborah L
Published: January 2017

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R&D spending and sources of funding of private US biopharmaceutical firms seeking to go public
Authors: Williams David R , Pouder Richard W
Published: January 2017

This study analyzes the relationship between the amount of research and development (R&D) spending in private US biopharmaceutical firms before they go public and whether or not these firms tap into external sources of funding for investment before an initial public offering. We focus our study on three specific sources of funding (venture capital investors, biopharmaceutical firm investors and strategic alliance partners) for two different time periods (one year prior to firms going public and cumulative years prior to going public). We found an increase in R&D spending over the course of the study and a positive relationship between R&D spending in the year prior to its going public and venture capital involvement. We also found a positive relationship between the cumulative amount spent on R&D and venture capital involvement and ownership by other biopharmaceutical firms. We use the literature on tradable assets and signaling theory to interpret the implications of our findings. For managers, the results suggest that if their goal is to send signals to future investors by way of spending greater amounts on R&D in the year prior to going public, then venture capital investors are more likely to be associated with this type of activity.
Exploratory assessment of the current EU regulatory framework for development of advanced therapies
Authors: Singh Pawanbir , BrÃ©vignon-Dodin Laure , Dash Satya P
Published: January 2017

The Advanced Therapy Medicinal Products (ATMP) Regulation provides a necessary regulatory framework for the commercialisation and use of regenerative medicine-based therapeutic products in the EU. However, concerns have been raised about the appropriateness of the regulatory strategy it has adopted to address different, complex and evolving categories of medicinal products. This article explores some of the potential shortfalls of the ATMP Regulation with regard to facilitating the research and development of advanced therapies in the present and in the future. It concludes that while providing a much needed harmonised regulatory framework for the companies operating in the sector, the new regulation has yet to demonstrate its capacity to keep up with radical technology changes.
Singapore â€“ Home base for expansion in Asia
Authors: Beh Kian-Teik
Published: January 2017

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Licensing intellectual property
Authors: Lawrence William F , White Barry S , Kowalski Thomas J , Lehnhardt Susan K , Zwally David A
Published: January 2017

This paper presents an overview of several issues concerning licensing intellectual property in or from the United States. We address (1) circumstances requiring government approval of an intellectual property licence; (2) licensing of intellectual property created with the help of government grants; and (3) the value of a patent licence in litigation settlements.
Pharmaceutical subsidisation and judicial review of the National Institute for Clinical Excellence
Authors: Best Richard
Published: January 2017

This paper outlines the nature and rules of the National Institute for Clinical Excellence (NICE) and, in the context of pharmaceuticals, assesses whether NICE is subject to judicial review, whether its members can be cross-examined, whether fresh evidence can be adduced at review hearings, the courts' likely approach to challenges to NICE's exercise of discretion on matters of substance and some aspects of the consultation obligations to which NICE is subject.
Key indicators of the German biopharmaceutical industry
Authors: Woerner Stephen , Reiss Thomas
Published: January 2017

The biotechnological paradigm has an enormous influence on the pharmaceutical industry, creating a new type of enterprise active in the biopharmaceutical sector. Building on a sound statistical basis, key indicators of this industry in Germany are discussed. The findings suggest an ongoing maturation process in the German biopharmaceutical industry, emphasising commercial orientation towards international markets. Technology portfolios are identified, suggesting four groups of companies producing or using similar products and technologies respectively. Based on these insights, conclusions are drawn on the expected future development of the sector.
Dealing with uncertainties in the biotechnology industry: The use of real options reasoning
Authors: Remer Sven , Ang Siah Hwee , Baden-Fuller Charles
Published: January 2017

Managers of biotechnology companies face great technological and market risks in making investment decisions. Traditional investment decision tools such as the discounted cash flow (DCF) approaches are often deemed insufficient in the face of the highly uncertain environment surrounding biotechnology projects. More recently, there is an increasing interest in real options approaches, which, in contrast to DCF, explicitly takes into account the managerial flexibility to respond to changing internal and external conditions during the course of the project. It is this flexibility that makes real options reasoning not only perceived to be superior for evaluating projects, but also for developing value-enhancing strategies. However, there is considerable confusion about when the real options approach might be applicable in practice, be it in a formal or an informal way. Based on insights derived from interviews with European biotechnology investors and managers, this study provides an overview of the potential benefits and limitations real options thinking has on evaluating and managing risky projects, particularly with respect to biotechnology companies.
Legal protection for inventions, designs and other information
Authors: Byrne Noel
Published: January 2017

Information is capable of being the stuff of intellectual property and related non-proprietary rights if the correct steps are taken to attract legal protection to the information, to have it recognized as information that the law will protect. Proprietary rights, for example patents for technical inventions (including technical features of computer programs), design rights for industrial designs, database rights for arrangement and contents of a database, and copyright for literary and artistic works (to name but two types of work protected by copyright) can be deployed along with non-proprietary rights over confidential information (including trade secrets), to form a protective screen around intangible assets. Depending on the circumstances, all, some, one or perhaps none of these rights may be available when one person seeks to prevent information belonging to him from being disclosed or used without his permission by another. The questions most often raised (and those addressed in this paper) by business executives and those carrying out research or development concern the acquisition of proprietary and non-proprietary rights and the protection of these intangible assets.
Consolidation revisited
Authors: Williams Alan
Published: January 2017

In 1998, the author produced two papers that argued that consolidation was a necessary activity for biotechnology companies to pay greater attention to. Three years later a further consideration of the subject seems worthwhile. Examples of successful consolidators are reviewed.
Legal and regulatory update
Authors: Wilkinson John
Published: January 2017

Presents updates on legal and regulatory issues concerning biotechnology and the pharmaceuticals industry in Europe as of September 2001. Proposals of the European Commission for changes in the Community pharmaceuticals legislation; Medications labeled as an Orphan Drug; Directives in biotechnological intellectual property.
Business models and investment trends in the biotechnology industry in Europe
Authors: Fisken Jane , Rutherford Jan
Published: January 2017

Presents a study that assessed the evolution of biotechnology company business models in relation to investment trends in the European public and private markets and the biotechnology industry, as of December 2001. Review of various aspects of several business models; Discussion on investment trends in public markets; Outlook for biotechnology business models.
Achieving venture returns through corporate spinouts
Authors: Ledbetter Ashley , Zipkin Ilan
Published: January 2017

As the biotechnology industry matures, the opportunity arises to establish companies by 'spinning out' undervalued but significant assets from larger biotechnology or pharmaceutical parent companies. Recognising the value in such assets and achieving rapid and meaningful returns on investments in corporate spinouts requires the infusion of the operational discipline of start-up companies along with the entrepreneurial spirit of a high-growth company. For this reason, spinout investing seems to be a natural fit with venture capitalists, whose perspective, experience and network can add tremendous value to a company at this stage. And yet spinout investing is also an area that can require significant cash commitments, which exceed the scale at which biotechnology venture capitalists have typically invested. With the emergence of a new breed of larger life science private equity firms that can now bring both the know-how and the capital to spinout investing, this is no longer an issue. Such investors are catalysing and driving the success of this growing class of investments to achieve the kinds of returns that will make these entities compelling opportunities for both parent companies and the limited partners of venture funds.
Riposte: FDA response to 'Yin, yang and the biopharmaceutical industry'
Authors: Rosenberg Amy S , Weiss Karen D , Lanthier Michael , Eastep Roger , Egan William , Goodman Jesse L , Woodcock Janet
Published: January 2017

In his editorial entitled 'Yin, yang, and the biopharmaceutical industry', Henry Miller attributes the three-year decline in biotechnology stocks to two factors: competition among biotechnology firms for a relatively small number of products, and Food and Drug Administration (FDA) regulatory actions. While we too are very concerned about the recent decline, we take issue with both the assertion that the FDA has played a large role in this decline and with the claims made to substantiate this assertion.
The Sarbanesâ€“Oxley Act and non-US issuers: Considerations for international companies
Authors: Gates Megan N
Published: January 2017

The Sarbanesâ€“Oxley Act of 2002 was signed into law by President George W. Bush on 30th July, 2002, in the wake of an unprecedented wave of corporate governance and accounting scandals that fundamentally shook public confidence in the integrity of the US securities markets. The Act's widespread effects continue to be analysed and dissected by companies and their advisors both in the USA and abroad. One of the most controversial elements of this legislation is its impact outside the borders of the USA, which is beginning to affect some of the most basic corporate governance and disclosure practices of companies worldwide. Foreign issuers subject to the Act must now begin to review their corporate governance practices carefully in order to ensure compliance with the new rules.
Book Review: Biotech Alliances: Bridging the R&D Gap
Authors: Scott Nerida
Published: January 2017

Biotech Alliances: Bridging the R&D Gap Stephen Seget Scrip Reports; PJB Publications, Richmond; 181pp
eClinical trials: The future is now
Authors: Marks Ronald G. , Conlon Michael
Published: January 2017

Clinical trial conduct today requires improvements in efficiency, accuracy and subject safety. These benefits are available as the industry makes clinical trial process changes through Web-based technology.
Marketspace: Leading biotechnology players, 2002â€“08: Key products, indications and technologies
Authors: Pavlou Alex K
Published: January 2017

For the full year 2002, the top ten biotechnology houses generated combined revenues (= royalties/licensing income + ethical or product sales; product sales includes both diagnostic and prescription drugs) of US$15.9bn, a 27 per cent increase over 2001. Using Datamonitor's proprietary forecasting methodology, the ethical sales of the ten leading biotechnology companies (Amgen, Genentech, Serono, Genzyme, Biogen, Chiron, MedImmune, Gilead, IDEC and Celltech) are forecast to grow from US$17.4bn in 2003 to US$32.7bn in 2008. Amgen and Genentech will lead the pack with ethical sales forecast to reach US$13.7bn and US$5.3bn, respectively. Amgen's Aranesp will be the leading biotechnology blockbuster, with sales forecast to reach US$3.1bn in 2008. Oncology and haematology/anaemia will be the most successful therapeutic indications, capturing more than 45 per cent of the group's ethical sales. When looking at the group's key technologies, rDNA proteins will maintain their leading position with more than half the ethical sales by 2008, although this dominance will decline as the market shares of antibody and small molecule-based drugs rise.
Understanding 'science and the public'
Authors: Gregory Jane
Published: January 2017

Public acceptance of the products of biotechnology is an important issue for the industry. This paper looks at relevant academic and policy developments in the field of public understanding of science, which considers the role of science in the public sphere. It traces the interaction of scientists, social scientists and the public in the move from early 'deficit' conceptions of public understanding to more recent positions in which the public are seen as active participants in a variety of contexts for science. These newer conceptualisations could usefully contribute to the biotechnology industry's ongoing task of establishing constructive relations with its various publics.
Business Model Innovation Opportunities for the Biopharmaceutical Industry: A Systematic Review
Authors: Downs James B. , Velamuri Vivek
Published: January 2017

Research on business model innovation for the biopharmaceutical industry continues to be an area of high global interest due to the combination of industry innovation challenges and global macroeconomic pressures.Â  Through the use of a systematic literature review the purpose of this research is to explore the universe of academic literature published from 1976 to 2013 that has addressed business model relevant factors and dynamics in the biopharmaceutical industry and inductively mine this literature for insights into the opportunities for business model innovation.Â  After identifying and reviewing 305 relevant publications, 12 categories were developed and key dynamics discussed.Â  The author finds that opportunities for business model innovation lie in five key areas, External Orientation, Learning Capabilities, Cluster Participation, Qualified Business Management Team and Organization Controls.Â  This research provides not only insight into opportunities for business model innovation specific to this industry but also can be used independently as a valuable reference tool for similar research.
Industry Partnerships, Key Success Factor to Win in the Biosimilars Space
Authors: Godrecka-Bareau Catherine
Published: January 2017

Over the past few years, biosimilars became the promised land of the pharmaceutical industry. Seven out of the top ten drugs are biologics. And all are about to lose patent protection by 2020, representing an underlying pool of $60bn branded sales. While it looks like the next Eldorado is in front of us, the biosimilars market is also a challenging opportunity, where the players have to deal with high R&D costs, unclear regulatory pathways, and uncertainty around business models. To make the biosimilars opportunity a sustainable market, it has to be profitable. In this article, I would like to discuss how innovative business models can help biosimiliars players to de-risk and ensure profitability. Looking at the example of the airline industry and analyzing the development chain for biosimilars, I would like to propose options to de-risk investments, optimize costs, and maximize sales.
Biotechnology, a strategic planning orphan: towards an effective strategy framework for biotechnology firms
Authors: Molloy Peter L , Johnson Lester W
Published: January 2017

Drug development biotechnology firms are most appropriately conceptualized as intermediaries in the pharmaceutical R&D value chain. Because they generally do not launch products themselves, generate significant revenues or compete in traditional markets, the established strategic planning frameworks and tools, such as SWOT, PESTLE and Gap analysis, have little utility. Porterâ€™s Five Forces Model (FFM) is a strategic planning framework that is prominent in texts, but has not been applied to biotechnology firms to any significant extent. This study reports on its application in one drug development biotechnology firm and concludes that, like the other techniques, FFM also fails for biotechnology firms. This is because it is rooted in traditional, highly-competitive markets, where profit maximization is the goal, and not the world of the R&D intermediary, where value creation is the measure of success. Despite the misfit of the FFM for biotechnology firms, the notion that strategy can be derived by consideration of the forces that influence success may provide the basis for a new strategy framework relevant to the business of biotechnology.
Leaving money on the table in venture-backed biotechnology IPOs
Authors: Jeppsson Hans Lennart
Published: January 2017

This study analyzes first-day returns (underpricing) for venture-backed biotechnology IPOs during 1980 through 2015. The result of this study shows that the average first-day return was 17.5 percent, which translates into an amount equal to $6.3 billion that was left on the table - nearly triple the $2.2 billion in underwriter fees. The study provides different theoretical explanations to the underpricing phenomenon and discusses why venture capitalists may be willing to accept leaving money on the table. The analysis also shows that IPOs with a large degree of underpricing are concentrated in hot IPO markets such as during 1999-2000 and more recently in the years 2014-2015. Notable, eight of the thirteen venture-backed biotechnology IPOs with the largest amount of money left on the table in the history of biotechnology went public during 2014-2015. From an investor perspective, if the degree of underpricing is an indicator of a pricing bubble, as was the case in 1999-2000, rational investors should at least be a little bit concerned about the state of the biotechnology equity market. From a management and venture capitalist perspective, issuing firms should at least consider using auctions as opposed to book-building to price and allocate IPOs to decrease the degree of underpricing and thereby the amount of money left on the table.
Biotech venture capital investments in public equities and performance
Authors: Jeppsson Hans Lennart
Published: January 2017

This study examines a large sample of venture investments in public equities (VIPEs) in the biotechnology and pharmaceutical industry over the period 1995-2014. The results of the study are threefold. First, and contrary to widely held beliefs, there has been no significant increase in the number of VIPEs over time. In fact, both in terms of dollar amount as well as the number of VIPE transactions have actually went down post the record year in 2009. Second, this study documents that returns profiles from the public venture capital market share many similarities to the returns in the private VC market: few big winners, but overall a high loss rate. Approximately seven investments out of ten in public firms generate a loss. Third, the analysis of private investments in public equities shows that venture capitalists outperform other competitors, such as hedge funds and mutual funds. From a management perspective, venture investments in public equity provide several benefits including providing an additional source of potential funding, aligning the investment horizon of venture capitalists with other long-term investors, certifying the quality of the firm and contributing to the long-term success.
The field-scale evaluation of herbicide-tolerant genetically modified crops conducted in the UK (1998â€“2003)
Authors: Turner Roger
Published: January 2017

In 1998 the UK Government, in conjunction with Supply Chain Initiative on Modified Agricultural Crops (SCIMAC, a cross-industry group representing the supply chain), established a large-scale programme to examine the impact of genetically modified herbicide-tolerant crops on farmland biodiversity. The trials programme lasted three years and was conducted by a consortium of scientists who were responsible to an independent scientific subcommittee. The background to the establishment of these trials is described and the political pressures facing the Government at that time and the reactions of key stakeholders are discussed.The field-scale evaluations were a pioneering project to examine the impact of genetically modified crops on farmland biodiversity. The exercise was one of the largest experiments ever carried out to measure the environmental impact of specific farming practices, and shows that robust results can be obtained, while the resultant database represents a wealth of ecological information on three important arable crops â€“ beet, maize and oilseed rape. It is clear that other such trials could be carried out to test other variables as part of a longer-term effort to steer farm management systems in ways more acceptable to society. However, in view of their costs (both to the UK Government and the technology providers) together with the adverse response by the environmental campaign groups, and the length of time needed to carry out the work, it seems unlikely that an exercise of similar scale will be undertaken in the near future.
Biotechâ€“pharma alliances: Strategies, structures and financing
Authors: Tyebjee Tyzoon , Hardin Jill
Published: January 2017

The drug discovery and development industry is under intense pressure to become more efficient and develop drugs better, faster, cheaper. Consequently, pharmaceutical and biotechnology companies are entering into alliances in an effort to utilise each other's talents, exploit each other's specialisations, and create more value. In this paper, the economics of the drug discovery and development cycle are examined to identify the economic and strategic logic of the alliances. The financial instruments commonly used to structure the alliances are discussed with example case studies.
Guidelines for Using Stainless Steel in the Water and Desalination Industries
Authors: Mackey Erin D. , Seacord Thomas F.
Published: January 2017

Stainless steels are corrosion‐resistant, but to take full advantage of their corrosion‐resistant properties, stainless steel piping and components must be properly specified, installed, and operated. The recommendations included in this article are intended to arm engineers and operators with a screening‐level tool for avoiding misapplication. To properly select the right grade of stainless steel for the various environmental conditions existing in different areas of the process, equipment, piping, and conveyance systems must be defined, including chlorides, pH, free chlorine in solution, bacteria, and temperature. Considering the environments that occur during idle, startup, normal operations, and shutdown conditions within treatment and conveyance facilities is also important. Once the stainless steel is specified and manufactured, proper care over its shipping, installation, and operation must be taken to protect the integrity of the materials to minimize corrosion.
From the editors
Authors: Value Language
Published: January 2017

From the Editors

TEACHING AND ASSESSING LISTENING SKILLS EFFECTIVELY IN THE LANGUAGE CLASSROOM: RESEARCH-BASED APPROACHERS

As stated in the last volume of the International Journal of Listening, “Compared with the other L2 skills of reading, writing and speaking, the field of listening is the youngest in terms of research” (Goh and Aryadoust, 2016: 6). This youth of listening skills development in the field of language teaching is partly due to availability of technological advances (audio recordings and videos) and (computer-based) teaching materials which were introduced at a later date in the classroom than paper-based materials. But a slower development of listening skills research is also determined by the fact that listening is a complex skill: it requires attention and concentration, it demands an instant recognition of an event and its related keywords, since vocabulary control and schemata knowledge (situation, topic knowledge and background knowledge) under which the listening input takes place are key factors in determining effective listening. Not only that, speaker factors (accent, intonation) and individual listener factors such as the listening strategies employed by an individual, gender or anxiety levels, are part of the listening skills construct. When we talk about assessing listening skills, together with these issues there is the question of task format in relation to both input and output requirements, the types of questions used in assessing listening skills or the number of times students are allowed to listen to a (video/audio) recording. All these aspects of listening make research in listening an intellectually and academically challenging work.
[Use of Kovaltry® in patients with Hemophilia A: clinical and economical aspects from the pivotal clinical trials]
Authors: D'Angiolella Lucia Sara , Molinari Angelo Claudio , Cortesi Paolo Angelo , Coppola Antonio , Mantovani Lorenzo Giovanni
Published: January 2017

[Article in Italian]
Les résonances de l’image et de l’imaginaire dans la composition musicale : une enquête polyphonique
Authors: Dallaire Frédéric
Published: January 2017

En mixant les propos de sept compositeurs contemporains (Brasset, Calon, Fano, Lepage, Lizée, Lussier, Piché), cette enquête s’intéresse aux interactions entre les mouvements visuels et les fluctuations sonores, aux enjeux de la composition musicale pour l’image, aux caractéristiques singulières de la perception audiovisuelle et aux effets de l’image (matérielle ou mentale) sur le processus de composition. En écoutant ces compositeurs décrire leur démarche de création, nous découvrons que l’image peut être une énergie, un matériau concret, un substrat, une résultante de l’écoute musicale, un artefact historique, une partition, un vecteur narratif, une strate dans un ensemble multimédiatique…
Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors
Authors: Mulcahy Levy Jean M , Zahedi Shadi , Griesinger Andrea M , Morin Andrew , Davies Kurtis D , Aisner Dara L , Kleinschmidt-DeMasters BK , Fitzwalter Brent E , Goodall Megan L , Thorburn Jacqueline , Amani Vladimir , Donson Andrew M , Birks Diane K , Mirsky David M , Hankinson Todd C , Handler Michael H , Green Adam L , Vibhakar Rajeev , Foreman Nicholas K , Thorburn Andrew
Published: January 2017

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors.
Present-day central African forest is a legacy of the 19th century human history
Authors: Morin-Rivat Julie , Fayolle Adeline , Favier Charly , Bremond Laurent , Gourlet-Fleury Sylvie , Bayol Nicolas , Lejeune Philippe , Beeckman Hans , Doucet Jean-Louis
Published: January 2017

The populations of light-demanding trees that dominate the canopy of central African forests are now aging. Here, we show that the lack of regeneration of these populations began ca. 165 ya (around 1850) after major anthropogenic disturbances ceased. Since 1885, less itinerancy and disturbance in the forest has occurred because the colonial administrations concentrated people and villages along the primary communication axes. Local populations formerly gardened the forest by creating scattered openings, which were sufficiently large for the establishment of light-demanding trees. Currently, common logging operations do not create suitable openings for the regeneration of these species, whereas deforestation degrades landscapes. Using an interdisciplinary approach, which included paleoecological, archaeological, historical, and dendrological data, we highlight the long-term history of human activities across central African forests and assess the contribution of these activities to present-day forest structure and composition. The conclusions of this sobering analysis present challenges to current silvicultural practices and to those of the future.
Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior
Authors: Wircer Einav , Blechman Janna , Borodovsky Nataliya , Tsoory Michael , Nunes Ana Rita , Oliveira Rui F , Levkowitz Gil
Published: January 2017

Proper response to stress and social stimuli depends on orchestrated development of hypothalamic neuronal circuits. Here we address the effects of the developmental transcription factor orthopedia (Otp) on hypothalamic development and function. We show that developmental mutations in the zebrafish paralogous gene otpa but not otpb affect both stress response and social preference. These behavioral phenotypes were associated with developmental alterations in oxytocinergic (OXT) neurons. Thus, otpa and otpb differentially regulate neuropeptide switching in a newly identified subset of OXT neurons that co-express the corticotropin-releasing hormone (CRH). Single-cell analysis revealed that these neurons project mostly to the hindbrain and spinal cord. Ablation of this neuronal subset specifically reduced adult social preference without affecting stress behavior, thereby uncoupling the contribution of a specific OXT cluster to social behavior from the general otpa−/− deficits. Our findings reveal a new role for Otp in controlling developmental neuropeptide balance in a discrete OXT circuit whose disrupted development affects social behavior.
Genetic and morphological analyses indicate that the Australian endemic scorpionUrodacus yaschenkoi(Scorpiones: Urodacidae) is a species complex
Authors: Luna-Ramirez Karen , Miller Adam D. , Rašić Gordana
Published: January 2017

Background

Australian scorpions have received far less attention from researchers than their overseas counterparts. Here we provide the first insight into the molecular variation and evolutionary history of the endemic Australian scorpionUrodacus yaschenkoi. Also known as the inland robust scorpion, it is widely distributed throughout arid zones of the continent and is emerging as a model organism in biomedical research due to the chemical nature of its venom.

Methods

We employed Bayesian Inference (BI) methods for the phylogenetic reconstructions and divergence dating among lineages, using unique haplotype sequences from two mitochondrial loci (COXI, 16S) and one nuclear locus (28S). We also implemented two DNA taxonomy approaches (GMYC and PTP/dPTP) to evaluate the presence of cryptic species. Linear Discriminant Analysis was used to test whether the linear combination of 21 variables (ratios of morphological measurements) can predict individual’s membership to a putative species.

Results

Genetic and morphological data suggest thatU. yaschenkoiis a species complex. High statistical support for the monophyly of several divergent lineages was found both at the mitochondrial loci and at a nuclear locus. The extent of mitochondrial divergence between these lineages exceeds estimates of interspecific divergence reported for other scorpion groups. The GMYC model and the PTP/bPTP approach identified major lineages and several sub-lineages as putative species. Ratios of several traits that approximate body shape had a strong predictive power (83–100%) in discriminating two major molecular lineages. A time-calibrated phylogeny dates the early divergence at the onset of continental-wide aridification in late Miocene and Pliocene, with finer-scale phylogeographic patterns emerging during the Pleistocene. This structuring dynamics is congruent with the diversification history of other fauna of the Australian arid zones.

Discussion

Our results indicate that the taxonomic status ofU. yaschenkoirequires revision, and we provide recommendations for such future efforts. A complex evolutionary history and extensive diversity highlights the importance of conservingU. yaschenkoipopulations from different Australian arid zones in order to preserve patterns of endemism and evolutionary potential.
From tameness to wariness: chemical recognition of snake predators by lizards in a Mediterranean island
Authors: Mencía Abraham , Ortega Zaida , Pérez-Mellado Valentín
Published: January 2017

Antipredatory defenses are maintained when benefit exceeds cost. A weak predation pressure may lead insular lizards to tameness.Podarcis lilfordiexhibits a high degree of insular tameness, which may explain its extinction from the main island of Menorca when humans introduced predators. There are three species of lizards in Menorca: the nativeP. lilfordi, only on the surrounding islets, and two introduced lizards in the main island,Scelarcis perspicillataandPodarcis siculus. In addition, there are three species of snakes, all introduced: one non-saurophagous (Natrix maura), one potentially non-saurophagous (Rhinechis scalaris) and one saurophagous (Macroprotodon mauritanicus). We studied the reaction to snake chemical cues in five populations: (1)P. lilfordiof Colom, (2)P. lilfordiof Aire, (3)P. lilfordiof Binicodrell, (4)S. perspicillata, and (5)P. siculus, ordered by increasing level of predation pressure. The three snakes are present in the main island, while onlyR. scalarisis present in Colom islet, Aire and Binicodrell being snake-free islets. We aimed to assess the relationship between predation pressure and the degree of insular tameness regarding scent recognition. We hypothesized thatP. lilfordishould show the highest degree of tameness,S. perspicillatashould show intermediate responses, andP. siculusshould show the highest wariness. Results are clear: neitherP. lilfordinorS. perspicillatarecognize any of the snakes, whileP. siculusrecognizes the scent ofM. mauritanicusand reacts to it with typical well-defined antipredatory behaviours as tail waving and slow motion. These results rise questions about the loss of chemical recognition of predators during island tameness and its related costs and benefits for lizards of insular habitats. In addition, this highlights the necessity for strong conservation measures to avoid the introduction of alien predators.
Cry1Ac and Vip3Aa proteins fromBacillus thuringiensistargeting Cry toxin resistance inDiatraea flavipennellaandElasmopalpus lignosellusfrom sugarcane
Authors: Lemes Ana Rita Nunes , Figueiredo Camila Soares , Sebastião Isis , Marques da Silva Liliane , da Costa Alves Rebeka , de Siqueira Herbert Álvaro Abreu , Lemos Manoel Victor Franco , Fernandes Odair Aparecido , Desidério Janete Apparecida
Published: January 2017

The biological potential of Vip and Cry proteins fromBacillusis well known and widely established. Thus, it is important to look for new genes showing different modes of action, selecting those with differentiated entomotoxic activity againstDiatraea flavipennellaandElasmopalpus lignosellus, which are secondary pests of sugarcane. Therefore, Cry1 and Vip3 proteins were expressed inEscherichia coli, and their toxicities were evaluated based on bioassays using neonate larvae. Of those, the most toxic were Cry1Ac and Vip3Aa considering the LC50values. Toxins fromE. coliwere purified, solubilized, trypsinized, and biotinylated. Brush Border Membrane Vesicles (BBMVs) were prepared from intestines of the two species to perform homologous and heterologous competition assays. The binding assays demonstrated interactions between Cry1Aa, Cry1Ac, and Vip3Aa toxins and proteins from the BBMV ofD. flavipennellaandE. lignosellus. Homologous competition assays demonstrated that binding to one of the BBMV proteins was specific for each toxin. Heterologous competition assays indicated that Vip3Aa was unable to compete for Cry1Ac toxin binding. Our results suggest that Cry1Ac and Vip3Aa may have potential in future production of transgenic sugarcane for control ofD. flavipennellaandE. lignosellus, but more research is needed on the potential antagonism or synergism of the toxins in these pests.
Effects of adults aging on word encoding in reading Chinese: evidence from disappearing text
Authors: Liu Zhifang , Pan Yun , Tong Wen , Liu Nina
Published: January 2017

The effect of aging on the process of word encoding for fixated words and words presented to the right of the fixation point during the reading of sentences in Chinese was investigated with two disappearing text experiments. The results of Experiment 1 showed that only the 40-ms onset disappearance of wordndisrupted young adults’ reading performance. However, for old readers, the disappearance of wordncaused disruptions until the onset time was 120 ms. The results of Experiment 2 showed that the disappearance of wordn + 1 did not cause disruptions to young adults, but these conditions made old readers spend more time reading a sentence compared to the normal display condition. These results indicated a reliable aging effect on the process of word encoding when reading Chinese, and that the encoding process in the preview frame was more susceptible to normal aging compared to that in the fixation frame. We propose that sensory, cognitive, and specific factors related to the Chinese language are important contributors to these age-related differences.
Detecting communicative intent in a computerised test of joint attention
Authors: Caruana Nathan , McArthur Genevieve , Woolgar Alexandra , Brock Jon
Published: January 2017

The successful navigation of social interactions depends on a range of cognitive faculties—including the ability to achieve joint attention with others to share information and experiences. We investigated the influence that intention monitoring processes have on gaze-following response times during joint attention. We employed a virtual reality task in which 16 healthy adults engaged in a collaborative game with a virtual partner to locate a target in a visual array. In theSearchtask, the virtual partner was programmed to engage in non-communicative gaze shifts in search of the target, establish eye contact, and then display a communicative gaze shift to guide the participant to the target. In theNoSearchtask, the virtual partner simply established eye contact and then made a single communicative gaze shift towards the target (i.e., there were no non-communicative gaze shifts in search of the target). Thus, only the Search task required participants to monitor their partner’s communicative intent before responding to joint attention bids. We found that gaze following was significantly slower in the Search task than the NoSearch task. However, the same effect on response times was not observed when participants completed non-social control versions of the Search and NoSearch tasks, in which the avatar’s gaze was replaced by arrow cues. These data demonstrate that the intention monitoring processes involved in differentiating communicative and non-communicative gaze shifts during the Search task had a measurable influence on subsequent joint attention behaviour. The empirical and methodological implications of these findings for the fields of autism and social neuroscience will be discussed.
A systematic review of animal predation creating pierced shells: implications for the archaeological record of the Old World
Authors: Kubicka Anna Maria , Rosin Zuzanna M. , Tryjanowski Piotr , Nelson Emma
Published: January 2017

Background

The shells of molluscs survive well in many sedimentary contexts and yield information about the diet of prehistoric humans. They also yield evidence of symbolic behaviours through their use as beads for body adornments. Researchers often analyse the location of perforations in shells to make judgements about their use as symbolic objects (e.g., beads), the assumption being that holes attributable to deliberate human behaviour are more likely to exhibit low variability in their anatomical locations, while holes attributable to natural processes yield more random perforations. However, there are non-anthropogenic factors that can cause perforations in shells and these may not be random. The aim of the study is compare the variation in holes in shells from archaeological sites from the Old World with the variation of holes in shells pierced by mollusc predators.

Methods

Three hundred and sixteen scientific papers were retrieved from online databases by using keywords, (e.g., ‘shell beads’; ‘pierced shells’; ‘drilling predators’); 79 of these publications enabled us to conduct a systematic review to qualitatively assess the location of the holes in the shells described in the published articles. In turn, 54 publications were used to assess the location of the holes in the shells made by non-human predators.

Results

Almost all archaeological sites described shells with holes in a variety of anatomical locations. High variation of hole-placement was found within the same species from the same site, as well as among sites. These results contrast with research on predatory molluscs, which tend to be more specific in where they attacked their prey. Gastropod and bivalve predators choose similar hole locations to humans.

Discussion

Based on figures in the analysed articles, variation in hole-location on pierced shells from archaeological sites was similar to variation in the placement of holes created by non-human animals. Importantly, we found that some predators choose similar hole locations to humans. We discuss these findings and identify factors researchers might want to consider when interpreting shells recovered from archaeological contexts.
Identifying niche‐mediated regulatory factors of stem cell phenotypic state: a systems biology approach
Authors: Ravichandran Srikanth , del Sol Antonio
Published: January 2017

Understanding how the cellular niche controls the stem cell phenotype is often hampered due to the complexity of variegated niche composition, its dynamics, and nonlinear stem cell–niche interactions. Here, we propose a systems biology view that considers stem cell–niche interactions as a many‐body problem amenable to simplification by the concept of mean field approximation. This enables approximation of the niche effect on stem cells as a constant field that induces sustained activation/inhibition of specific stem cell signaling pathways in all stem cells within heterogeneous populations exhibiting the same phenotype (niche determinants). This view offers a new basis for the development of single cell‐based computational approaches for identifying niche determinants, which has potential applications in regenerative medicine and tissue engineering.
Bidirectional communication between sensory neurons and osteoblasts in an in vitro coculture system
Authors: Kodama Daisuke , Hirai Takao , Kondo Hisataka , Hamamura Kazunori , Togari Akifumi
Published: January 2017

Recent studies have revealed that the sensory nervous system is involved in bone metabolism. However, the mechanism of communication between neurons and osteoblasts is yet to be elucidated. In this study, we investigated the signaling pathways between sensory neurons of the dorsal root ganglion (DRG) and the osteoblast‐like MC3T3‐E1 cells using an in vitro coculture system. Our findings indicate that signal transduction from DRG‐derived neurons to MC3T3‐E1 cells is suppressed by antagonists of the AMPA receptor and the NK1 receptor. Conversely, signal transduction from MC3T3‐E1 cells to DRG‐derived neurons is suppressed by a P2X7 receptor antagonist. Our results suggest that these cells communicate with each other by exocytosis of glutamate, substance P in the efferent signal, and ATP in the afferent signal.