bluuebunny/crossref_metadata_2025 huggingface dataset:
Multivariate statistics
Authors: El Karoui Noureddine
Published: August 2018

This article considers some classical and more modern results obtained in random matrix theory (RMT) for applications in statistics. In the classic paradigm of parametric statistics, data are generated randomly according to a probability distribution indexed by parameters. From this data, which is by nature random, the properties of the deterministic (and unknown) parameters may be inferred. The ability to infer properties of the unknown Σ (the population covariance matrix) will depend on the quality of the estimator. The article first provides an overview of two spectral statistical techniques, principal components analysis (PCA) and canonical correlation analysis (CCA), before discussing the Wishart distribution and normal theory. It then describes extreme eigenvalues and Tracy–Widom laws, taking into account the results obtained in the asymptotic setting of ‘large p, large n’. It also analyses the results for the limiting spectra of sample covariance matrices..
Symmetry classes
Authors: Zirnbauer Martin R.
Published: August 2018

This article examines the notion of ‘symmetry class’, which expresses the relevance of symmetries as an organizational principle. In his 1962 paper The threefold way: algebraic structure of symmetry groups and ensembles in quantum mechanics, Dyson introduced the prime classification of random matrix ensembles based on a quantum mechanical setting with symmetries. He described three types of independent irreducible ensembles: complex Hermitian, real symmetric, and quaternion self-dual. This article first reviews Dyson’s threefold way from a modern perspective before considering a minimal extension of his setting to incorporate the physics of chiral Dirac fermions and disordered superconductors. In this minimally extended setting, Hilbert space is replaced by Fock space equipped with the anti-unitary operation of particle-hole conjugation, and symmetry classes are in one-to-one correspondence with the large families of Riemannian symmetric spaces.
Random matrix theory and ribonucleic acid (RNA) folding
Authors: Vernizzi Graziano , Orland Henri
Published: August 2018

This article discusses a series of recent applications of random matrix theory (RMT) to the problem of RNA folding. It first provides a schematic overview of the RNA folding problem, focusing on the concept of RNA pseudoknots, before considering a simplified framework for describing the folding of an RNA molecule; this framework is given by the statistic mechanical model of a polymer chain of L nucleotides in three dimensions with interacting monomers. The article proceeds by presenting a physical interpretation of the RNA matrix model and analysing the large-N expansion of the matrix integral, along with the pseudoknotted homopolymer chain. It extends previous results about the asymptotic distribution of pseudoknots of a phantom homopolymer chain in the limit of large chain length.
Complex networks
Authors: Rodgers Geoff , Nagao Taro
Published: August 2018

This article deals with complex networks, and in particular small world and scale free networks. Various networks exhibit the small world phenomenon, including social networks and gene expression networks. The local ordering property of small world networks is typically associated with regular networks such as a 2D square lattice. The small world phenomenon can be observed in most scale free networks, but few small world networks are scale free. The article first provides a brief background on small world networks and two models of scale free graphs before describing the replica method and how it can be applied to calculate the spectral densities of the adjacency matrix and Laplacian matrix of a scale free network. It then shows how the effective medium approximation can be used to treat networks with finite mean degree and concludes with a discussion of the local properties of random matrices associated with complex networks.
Southern Europe (Italy, Iberian Peninsula, France)
Authors: Hespanha António
Published: August 2018

In this chapter, law is taken as a set of related communicative systems. The idea of legal communicative systems or spheres emphasizes the coexistence of a plurality of laws according to factors of differentiation other than global entities, mostly related to a nation state pre-comprehension, like ‘races’ or ‘nations’, ‘kingdoms’. What would matter would be the setting of shared dispositives of ‘telling (uncovering, creating) law’. This approach problematizes established assumptions, like the separation between ‘romanistic’ and ‘germanistic’ laws, the all-inclusiveness of ‘national’ or state laws, the unity of learned law. Conversely, it supports emergent research interests on: the artificiality and complexity of ‘nations’, the porosity of ‘Germanic’ law to ‘foreign’ influences, the impact of materialities of legal communication over form and even content, the coexistence in a same territory of different legal communities, separated by communicative divides.
Natural Law in Early Modern Legal Thought
Authors: Ibbetson David
Published: August 2018

Natural law thinking in the early modern world had two principal roots: Greco-Roman moral philosophy and Roman law. These two strands came together in sixteenth-century Spain, from where they influenced the Dutchman Hugo Grotius. Grotius can be seen as the channel through which this thinking reached a pan-European audience. His works, and the works of his followers, came to have an enormous influence on the development of legal thought and practice after the seventeenth century. Ideas of natural law were no longer regarded as dependent on God’s will. A rational structure could be derived from self-evident premises in the law of nature and identification of concrete rules of natural law was regarded as the work of human reason. These features, coupled with its seeming moral objectivity, allowed natural law to provide a template for positive legal systems, and fuelled the move towards codification of law in eighteenth-century Europe.
Criminal Law
Authors: Meccarelli Massimo
Published: August 2018

This chapter aims to study features and development of criminal law in the medieval and modern ages. The emergence, at the end of the eighteenth century, of the state monopoly on punishment, connected with the establishment of the statutory law as an ordering factor, represents a historical turn. Before, criminal law—much more than to the exercise of a right to punish—is related to the problem of determining justice in order to produce a public space substitute for revenge. The chapter, considering this different foundation, analyses the ordering factors structuring the criminal law system. It then focuses on peculiar features of the criminal trial and on key aspects such as the role of the judge, the sanctions regimes, the taxonomy of the crimes, and the regimes of proof. Some cursory remarks, as to how the criminal legal order turns into a system under a state monopoly, serve as a conclusion.
The Constitutional State
Authors: Gosewinkel Dieter
Published: August 2018

At the turn of the nineteenth century, the constitutional state took its origin from a revolution against absolutist rule and feudal inequality. ‘Constitution’ as a revolutionary new concept of law meant as an ideal-type: written, supreme, secular law, decided by the people and regulating all public power. Constitutional monarchy was the dominant type of constitutional state in Europe throughout the nineteenth century. It was marked by a fundamental dualism between monarchical and parliamentary power, which tended towards parliamentarization and came to an end with complete constitutionalization and democratization of European states as an outcome of the First World War. While the post-war years represented the apex of European constitutionalism, the deep European crisis of the 1930s with the rise of dictatorship destroyed the core function of constitutionalism, to legally bind state power, which came to be restored only gradually after 1989 for the whole of Europe.
Colonial Criminal Law and Other Modernities
Authors: Dubber Markus D.
Published: August 2018

This chapter reflects on various traditional approaches to the historical study of European criminal law in the nineteenth and twentieth centuries. It examines several ways of naming and framing the subject matter, along with ways of ‘covering’ it along a set of by now fairly well-established narrative paths that generally reflect a quietly reassuring Whiggishness. It then lays out an alternative, two-track, conception of ‘modern’ European criminal legal history. It does this by taking an upside-down—or outside-in—view of the subject, by focusing on an understudied, but fascinating, project of European criminal law: the invention, implementation, and evolution of colonial criminal law.
Global Legal History
Authors: Duve Thomas
Published: August 2018

As shown in the previous chapters, our image of European legal history itself has evolved as a result of the nineteenth-century national legal historiographies and their translation into the political and intellectual constellations of the mid twentieth century European movement. It is only more recently that the path-dependencies resulting from this tradition have been problematized and that stronger claims have been made to situate European legal history within global perspectives. This chapter presents an overview of both this development and what might be called ‘global perspectives on European legal history’. To do so, it traces back how the category ‘Europe’ became the most important spatial framing of transnational legal history. It provides an overview about how leading scholars constructed the relation between Europe and other world areas. It sketches out current ways of placing European legal history in global perspectives today.
Customary Law and the Influence of the Ius Commune in High and Late Medieval East Central Europe
Authors: Korpiola Mia
Published: August 2018

Secular law remained largely customary and uncodified in east central Europe. While much of south-eastern Europe had remained Christian ever since Roman times, most of east central Europe was Christianized during the high Middle Ages. The Baltic region came later, Lithuania only being converted after 1387. South-eastern Europe was influenced first by Byzantine and then Italian law. In much of east central Europe secular law was based on Slavic customs, later influenced by canon law and German law. The Sachsenspiegel, Schwabenspiegel, and German town law spread to the whole region alongside the German colonization of east central Europe. Towns functioned as conduits of German and learned law. Certain territorial rulers actively promoted Roman law and (partial) codification, while the local nobility preferred uncodified customary law. In addition to foreign university studies, the fourteenth-century universities of Prague and Krakow, cathedral chapters, and notaries helped disseminate the ius commune into the region.
Ancient Greek Law
Authors: Gagarin Michael
Published: August 2018

This chapter gives an overview of law in ancient Greece. After discussing the unity of Greek law and scholarship on Greek law, it reviews the evidence for law in Gortyn (in Crete), including the Gortyn Law Code, in Sparta, and at greater length in Athens, which is best documented. Athens had a highly democratic legal system. Legislation was enacted by an Assembly open to all citizens, laws were written and publicly displayed, plaintiffs and defendants pleaded their own cases, and trials were judged by juries of 200 or more. Private disputes first went to arbitration. When no individual victim existed (e.g. public embezzlement), anyone could prosecute. There were no professional judges, prosecutors, or advocates, but the rule of law was largely observed. In Hellenistic Greece, law in cities remained relatively unchanged but in newly settled areas like Egypt, law developed very differently. Greek law had little influence on later law.
The Secretariat
Authors: Jonah James O. C. , Hill Amy Scott
Published: August 2018

This chapter outlines the genesis of the independent international civil service and the history of this concept in the form of the UN Secretariat. It shows how successive secretaries-general have interpreted their role and balanced member-state demands, thereby shaping the functions, structures, and internal workings of the Secretariat over time. It also highlights the interests of member states in many aspects of the Secretariat’s management and the politics of its never-ending ‘reform’ process, noting that successful reform requires the investment of real political capital by the Secretary-General. The chapter describes the selection of the Secretary-General as a window onto the uneasy balance between the Secretariat’s dependence on member states and its Charter obligations.
Bretton Woods Institutions
Authors: Woods Ngaire
Published: August 2018

The IMF and World Bank were created at the end of World War II to support economic stability, trade, and reconstruction around the world. Subsequently, they became strongly associated with globalization and the opening up of economies to trade, capital flows, and foreign investment. This ensured support from wealthy governments and business but sharp criticism about their impacts on inequality, environmental damage, and corruption. Each now faces a more existential challenge due to the shifting power and focus of their member states. What remains constant is the need for each to strengthen its legitimacy, refocus its mandate, and work better with other organizations.
World Trade Organization
Authors: Wilkinson Rorden
Published: August 2018

The World Trade Organization (WTO) is a complex organization with a plethora of apparent contradictions. This chapter offers an introduction to the WTO and its role in governing global trade. It examines the organization’s evolution from a failed post-war attempt to create the International Trade Organization (ITO), the emergence in the ITO’s place of the General Agreement on Tariffs and Trade (GATT), and the eventual creation of today’s WTO. The chapter then explores its organizational fundamentals as well as some of the issues likely to loom largest on the global trade agenda in the coming years before offering some concluding comments.
Regional Organizations
Authors: Sidhu Waheguru Pal Singh
Published: August 2018

The UN Charter provides a prominent role for ‘regional agencies or arrangements’ under Chapters VI and VIII. While regional actors played a limited role during the Cold War, the post-Cold War period has witnessed the regionalization of peace operations. Today regional organizations, particularly the African Union, play an equal if not more prominent role on the ground than the UN in peace operations. While the involvement of regional organizations offers several benefits to the overstretched UN, it also carries significant risks. Moreover, unless several proposed reforms are implemented, the effectiveness of UN-regional ‘partnership peacekeeping,’ or hybrid operations, is likely to remain impaired.
Origins of the United Nations
Authors: Morris Justin
Published: August 2018

This chapter analyzes the transformational journey that plans for the United Nations undertook from summer 1941 to the San Francisco Conference of 1945 at which the UN Charter was agreed. Prior to the conference, the ‘Big Three’ great powers of the day—the United States, the Soviet Union, and the United Kingdom—often struggled to establish the common ground on which the UN’s success would depend. However, their debates were only the start of the diplomatic travails which would eventually lead to the establishment of the world organization that we know today. Once gathered at San Francisco, the fifty delegations spent the next two months locked in debate over issues such as the role of international law; the relationship between the General Assembly and Security Council; the permanent members’ veto; and Charter amendment. One of modern history’s most important diplomatic events, its outcome continues to resonate through world politics.
Arms Control and Disarmament
Authors: Krause Keith
Published: August 2018

This chapter evaluates the achievements and limitations of the United Nations (including the Conference on Disarmament) in the field of disarmament, emphasizing the UN’s role as part of broader efforts to control arms as a means to achieve international peace and security. It presents an overview of UN disarmament efforts and discusses specific cases where progress was achieved, such as the Nuclear Non-Proliferation Treaty (NPT), the Chemical Weapons Convention (CWC), the Arms Trade Treaty, and efforts to tackle the problems of anti-personnel land mines and small arms and light weapons. Finally, it draws out the implications for international relations of the UN experience with formal multilateral arms control, disarmament and security-building processes by evaluating its role as a negotiating forum, a norm setter, an implementing agency, or an instrument of great power security governance.
Peace Operations
Authors: Gowan Richard
Published: August 2018

UN peace operations face an uncertain future. Peacekeeping deployments have been through cycles of expansion and contraction since the 1950s. Over the last two decades, the UN has been heavily engaged in a series of sizeable operations, primarily in Africa. Peacekeepers have struggled to engender sustainable peace in cases such as the Democratic Republic of Congo and South Sudan. This reflects organizational weaknesses in the UN peacekeeping system, questions over the limits of military action by peacekeeping forces in volatile environments, and tensions with the fragile governments that the UN is mandated to support. There is a new emphasis on lighter political missions as an alternative to large blue helmet forces. But history shows that the evolution of peace operations is rarely linear or predictable.
Sanctions
Authors: Lopez George A.
Published: August 2018

This chapter examines trends and themes that have developed over the past quarter century in the use of economic sanctions by the UN Security Council. It emphasizes targeted financial sanctions, arms embargoes, and commodity sanctions as the most consistently imposed and the most thoroughly refined measures in the Council’s repertoire. It focuses on the utility and dilemmas of these sanctions in controlling international terrorism, preventing or reversing nuclear proliferation, and dealing with the perpetration of mass violence and atrocities against civilians. Finally, the chapter analyzes the challenges the UN faces in continuing and extending these particular techniques for advancing peace and security.
Humanitarian Intervention and the Responsibility to Protect
Authors: Thakur Ramesh
Published: August 2018

Cross-border military intervention is a recurring feature throughout history. Often, geopolitical and commercial calculations were cloaked in the language of ‘humanitarian intervention.’ After decolonization, developing countries embedded non-intervention as a peremptory norm. Many tyrants then used sovereignty as a shield behind which to commit atrocities with impunity. When the North Atlantic Treaty Organization intervened to protect victims of Serbian atrocities in Kosovo, the Non-Aligned Movement denounced any right of humanitarian intervention. To reconcile the two competing imperatives, the International Commission on Intervention and State Sovereignty proposed the principle of the ‘responsibility to protect’ to permit UN-authorized protective interventions while consolidating a rules-based order. Although much improved, however, dilemmas remain about when and by whom force can be used inside borders to guarantee human protection.
Crime and Criminal Justice
Authors: Romaniuk Peter
Published: August 2018

This chapter surveys the institutions, mandates, norms, and rules that comprise UN action in the fields of crime prevention, criminal justice, drug control, and transnational organized crime. These measures have assumed more prominence on the international agenda over time, as member states have sought collaborative responses to common problems, while advancing their interests to influence the form and substance of cooperation. The UN’s contribution is vital given the persistent challenge that criminal non-state actors pose not only to states but also the international system. The overarching objectives of UN action on crime and criminal justice are not merely to prevent and suppress crime and punish offenders but also proactively to nurture the development of ‘responsible statehood.’
Health and Infectious Disease
Authors: Burci Gian Luca
Published: August 2018

The chapter offers a critical review of the development of a legal and political framework for the prevention and control of international disease outbreaks. Historically, such development focused on the role and functions of the World Health Organization, culminating in the 2005 revision of the International Health Regulations. The effectiveness of that framework has come under intense criticism as a result of the inadequate international response to the 2014–2016 Ebola outbreak in West Africa and has led to global efforts to build a more credible system of global health security. The chapter analyzes recent legal and policy developments in this area, with particular emphasis on the inclusion of health threats into the international security agenda and the complex interactions between the international protection of biodiversity and sharing of human pathogens for public health protection.
Legal Perspectives
Authors: Alvarez José E.
Published: August 2018

This chapter surveys how international legal scholars have catalogued and sought to explain the legal impact of the UN even though its political and judicial organs have not been delegated the power to make law. It explains how the UN attempts to adhere to, but also challenges, the traditional sources of international law—treaties, custom, and general principles—contained in the Statute of the International Court of Justice. It enumerates how the turn to UN system organizations—amidst newly empowered non-state actors, increasing resort to ‘soft’ or ‘informal’ norms, and recourse to institutionalized processes—have led to distinct legal frameworks such as process or deliberative theories, interdisciplinary ‘law and’ approaches, feminist and ‘Third World’ critiques, and scholarly work that renews attention to or revises legal positivism.
Democracy and Good Governance
Authors: Knight W. Andy
Published: August 2018

This chapter examines the UN’s role in promoting and encouraging democracy and good governance. The world organizations is in a pivotal position to help promote and strengthen the global norm that posits that democracy validates the quality of governance today. In order to be considered ‘democratic,’ governments should not only hold periodic free and fair elections and demonstrate the ability to govern inclusively and humanely. In addition, they should also respect human rights and the rule of law. Concurrently, the chapter argues that the UN should practice what it preaches and address its own democratic deficit, even as it helps to strengthen democracy at the national level.
Sustainable Development Goals
Authors: Fukuda-Parr Sakiko
Published: August 2018

The 2015 agreement on the Sustainable Development Goals (SDGs) was an ambitious and inclusive agenda that went beyond the poverty agenda of the Millennium Development Goals to incorporate climate change, infrastucture, and governance issues, and redefined development as a universal challenge. The SDGs are also the latest in a series of UN goal-setting processes. This chapter examines the strengths and pitfalls of such global goal-setting and the limitations of capturing development priorities in a single number. It begins with an overview of the SDGs as an agenda, purpose, and political process, and then evaluates global goal-setting as a specific policy tool for elaborating and promoting global development priorities.
Evolution in Knowledge and Norms
Authors: Gordenker Leon , Jönsson Christer
Published: August 2018

The UN system produces abundant, easily accessible information about itself and about the world at large. The statistics and databases compiled in the UN system help monitor progress on its goals for global economic and social development. Moreover, the UN contributes to knowledge through its training, education, and research initiatives. Academia remains a key producer of knowledge about the UN, and the introduction of the concept of global governance has stimulated a renewed focus on the organization. Today, electronic and social media are important sources of popular knowledge. Despite ‘scandals’ and negative publicity, the UN enjoys public support around the world. There seems to be no firm correlation between popular attitudes and knowledge.
General Assembly
Authors: Peterson M. J.
Published: August 2018

This chapter looks at how the General Assembly fulfils its tasks of global level deliberation and organizational oversight of other UN bodies through summaries of its formal rules and evolving procedures. Its substantive conclusions have always been determined by the preferences of whatever coalition of two-thirds of the total UN membership controls the Assembly. The practical effect of pronouncements depends on the ability of states in the supporting coalition to implement them through their own actions. Analysts continue to advance proposals to enhance the Assembly’s formal authority vis-à-vis member states and other UN bodies. However, convergence on accepting the greater centralization of global governance needed to adopt them remains much less likely than continued pursuit of global governance through trans-governmental and transnational networks of the willing. For the General Assembly to be a useful deliberative body, its members should reconsider how they use it for both deliberative and supervisory functions.
Economic and Social Council
Authors: Rosenthal Gert
Published: August 2018

This chapter offers an overview of the ECOSOC since its establishment as one of the six principal organs of the United Nations. It explores its functions, structure, organization, working methods, and evolution over time. It also contains an analysis of ECOSOC’s impact, and especially the difficulties encountered over its lifetime to resolve an inherent tension with the General Assembly, given the overlapping in both of these organs’ remit and their ambiguous relationship. Those tensions were the drivers of numerous reform proposals over the years in the quest for greater relevance. Especially noteworthy is the outburst of initiatives since 2005 to find a firmer anchor to ECOSOC’s role in the wider governance structure of the United Nations, which suggest placing the ECOSOC decisively ‘under the authority of the General Assembly.’
James and Epistemic Pluralism
Authors: Skrupskelis Ignas Kęstutis
Published: August 2018

James’s account of truth is pluralistic. He holds that there are different kinds of truth, with truth by correspondence being only one. He does not provide a complete list of the kinds. Central for James is the problem of reference because of his concern to refute Royce’s argument for the Absolute. Referential assertions are true if and only if there are experienceable paths which if traversed would lead into the presence of the object. Such assertions anchor knowledge. Scientific theories are true if they are anchored—that is, fit the facts, can be integrated into the established system of beliefs, and are simpler and more fruitful than any alternatives. Religious beliefs cannot be in conflict with facts and science. But they must carry with them a sense of authority and illumination and meet our moral needs. The will to believe is not a question of truth, but it allows us to hold “over-beliefs,” at our own risk, so as not to impoverish human experience.
ICTV Virus Taxonomy Profile: Globuloviridae
Authors: Prangishvili David , Krupovic Mart ,   ICTV Report Consortium
Published: August 2018

The family Globuloviridae comprises enveloped viruses with linear, double-stranded DNA genomes of about 21–28 kbp. The virions are spherical with a diameter of 70–100 nm. No information is available about genome replication. Globuloviruses infect hyperthermophilic archaea belonging to the genera Pyrobaculum and Thermoproteus, which thrive in extreme geothermal environments. Infection does not cause lysis of host cells and is noncytocidal. The viral genome does not integrate into the host chromosome. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Globuloviridae, which is available at www.ictv.global/report/globuloviridae.
Whole blood transcriptome analysis reveals footprints of cattle adaptation to sub-arctic conditions
Authors: Pokharel Kisun , Weldenegodguad Melak , Popov Ruslan , Honkatukia Mervi , Huuki Hanna , Lindeberg Heli , Peippo Jaana , Reilas Tiina , Zarovnyaev Stepan , Kantanen Juha
Published: August 2018

Indigenous cattle breeds in northern Eurasia have adapted to harsh climate conditions. The local breeds are important genetic resources with cultural and historical heritages, and therefore, their preservation and genetic characterization are important. In this study, we aim to identify genes and biological processes that are important for their adaptation to the cold and harsh conditions. For this purpose, we profiled the whole-blood transcriptome of two native breeds and one commercial breed using high-throughput RNA sequencing. More than 15,000 genes were identified, of which 2, 89, and 162 genes were significantly upregulated exclusively in Northern Finncattle, Yakutian cattle and Holstein cattle, respectively. The functional classification of these significantly differentially expressed genes identified several biological processes and pathways related to signalling mechanisms, cell differentiation, and host-pathogen interactions that, in general, point towards immunity and disease resistance mechanisms. The gene expression pattern observed in Northern Finncattle was more similar to that of Yakutian cattle, despite sharing similar living conditions as the Holstein cattle included in our study. In conclusion, our study identified unique biological processes in these breeds that help them to adapt and survive in sub-arctic environments.
Functional In vivo Single-cell Transcriptome (FIST) Analysis Reveals Molecular Properties of Light-Sensitive Neurons in Mouse V1
Authors: Liu Jianwei , Pan Na , Sun Le , Wang Mengdi , Zhang Junjing , Zuo Zhentao , He Sheng , Wu Qian , Wang Xiaoqun
Published: August 2018

Vision formation is classically based on projections from the retinal ganglion cells (RGC) to the lateral geniculate nucleus (LGN) and the primary visual cortex (V1). Although the cellular information of the retina and the LGN has been widely studied, the transcriptome profiles of single neurons with specific functions in V1 still remain unknown. Some neurons in mouse V1 are tuned to light stimulus. To determine the molecular properties of light-stimulated neurons in layer 2/3 of V1, we developed a method of functionalin vivosingle-cell transcriptome (FIST) analysis that integrates sensory evoked calcium imaging, whole-cell electrophysiological patch-clamp recordings, single-cell mRNA sequencing and three-dimensional morphological characterization in a live mouse, based on a two-photon microscope system. In our study, 58 individual cells from layer 2/3 of V1 were identified as either light-sensitive (LS) or non-light-sensitive (NS) by single-cell light-evoked calcium evaluation and action potential spiking. The contents of every single cell after individual functional tests were aspirated through the patch-clamp pipette for mRNA sequencing. Furthermore, the three-dimensional (3-D) morphological characterizations of the neurons were reconstructed in the live mouse after the whole-cell recordings. Our sequencing results indicated that V1 neurons with high expression of genes related to transmission regulation, such asRtn4r,Nr4a1,and genes involved in membrane transport, such as Na+/K+ATPase, NMDA-type glutamatergic receptor, preferentially respond to light stimulation. Our findings demonstrate the ability of FIST analysis to characterize the functional, morphological and transcriptomic properties of a single cell in alive animal, thereby providing precise neuronal information and predicting its network contribution in the brain.
Deterministic Nature of Cellular Position Noise DuringC. elegansEmbryogenesis
Authors: Li Xiaoyu , Zhao Zhiguang , Xu Weina , Fan Rong , Xiao Long , Ma Xuehua , Du Zhuo
Published: August 2018

Individuals with identical genotypes exhibit great phenotypic variability known as biological noise, which has broad implications. While molecular-level noise has been extensively studied, in-depth analysis of cellular-level noise is challenging. Here, we present a systems-level quantitative and functional analysis of noise in cellular position during embryogenesis, an important phenotype indicating differentiation and morphogenesis. We show that cellular position noise is deterministic, stringently regulated by intrinsic and extrinsic mechanisms. The noise level is determined by cell lineage identity and is coupled to developmental properties including embryonic localization, cell contact, and left-right symmetry. Cells follow a concordant low-high-low pattern of noise dynamics, and fate specification triggers a global down-regulation of noise that provide a noise-buffering strategy. Noise is stringently regulated throughout embryogenesis, especially during cell division and cell adhesion and gap junctions function to restrict noise. Collectively, our study reveals system properties and regulatory mechanisms of cellular noise control during development.
Voxelwise encoding models with non-spherical multivariate normal priors
Authors: Nunez-Elizalde Anwar O. , Huth Alexander G. , Gallant Jack L.
Published: August 2018

Predictive models for neural or fMRI data are often fit using regression methods that employ priors on the model parameters. One widely used method is ridge regression, which employs a spherical Gaussian prior that assumes equal and independent variance for all parameters. However, a spherical prior is not always optimal or appropriate. There are many cases where expert knowledge or hypotheses about the structure of the model parameters could be used to construct a better prior. In these cases, non-spherical Gaussian priors can be employed using a generalized form of ridge known as Tikhonov regression. Yet Tikhonov regression is only rarely used in neuroscience. In this paper we discuss the theoretical basis for Tikhonov regression, demonstrate a computationally efficient method for its application, and show several examples of how Tikhonov regression can improve predictive models for fMRI data. We also show that many earlier studies have implicitly used Tikhonov regression by linearly transforming the regressors before performing ridge regression.
Enhanced axonal Neuregulin-1 type-III signaling ameliorates disease severity in a CMT1B mouse model
Authors: Scapin Cristina , Ferri Cinzia , Pettinato Emanuela , Zambroni Desiree , Bianchi Francesca , Carro Ubaldo Del , Belin Sophie , Caruso Donatella , Mitro Nico , Pellegatta Marta , Taveggia Carla , Schwab Markus H. , Nave Klaus-Armin , Feltri M. Laura , Wrabetz Lawrence , D’Antonio Maurizio
Published: August 2018

Charcot–Marie–Tooth neuropathies (CMTs) are a group of genetic disorders that affect the peripheral nervous system (PNS) with heterogeneous pathogenesis and no available treatment. Axonal Neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here, we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain of function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor TACE/ADAM17, also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.
Human frontoparietal cortex represents behaviorally-relevant target status during invariant object recognition
Authors: Henderson Margaret , Serences John T.
Published: August 2018

Searching for items that are useful given current goals, or “target” recognition, requires an observer to generalize across identity-preserving transformations such as viewpoint changes, as well as to incorporate contextual information. While past work has found target recognition signals in areas of ventral visual cortex, it is not clear whether these signals support performance on demanding tasks that require invariant, flexible search. Here, we used a task that required subjects to match novel object stimuli based on invariant features (identity and viewpoint). Based on multivariate fMRI analyses, the data suggest that the multiple-demand (MD) network, including sub-regions of parietal and frontal cortex, encodes invariant representations of an object’s status as a target. Furthermore, target information in MD regions, but not early or ventral visual cortex, was higher on correct compared to incorrect trials, suggesting a strong link between MD target signals and behavior.
Reliable variant calling during runtime of Illumina sequencing
Authors: Loka Tobias P. , Tausch Simon H. , Renard Bernhard Y.
Published: August 2018

The sequential paradigm of data acquisition and analysis in next-generation sequencing leads to high turnaround times for the generation of interpretable results. We combined a novel real-time read mapping algorithm with fast variant calling to obtain reliable variant calls still during the sequencing process. Thereby, our new algorithm allows for accurate read mapping results for intermediate cycles and supports large reference genomes such as the complete human reference. This enables the combination of real-time read mapping results with complex follow-up analysis. In this study, we showed the accuracy and scalability of our approach by applying real-time read mapping and variant calling to seven publicly available human whole exome sequencing datasets. Thereby, up to 89% of all detected SNPs were already identified after 40 sequencing cycles while showing similar precision as at the end of sequencing. Final results showed similar accuracy to those of conventionalpost-hocanalysis methods. When compared to standard routines, our live approach enables considerably faster interventions in clinical applications and infectious disease outbreaks. Besides variant calling, our approach can be adapted for a plethora of other mapping-based analyses.
Dragotcytosis: Elucidation of the Mechanism forCryptococcus neoformansMacrophage-to-Macrophage Transfer
Authors: Dragotakes Quigly , Fu Man Shun , Casadevall Arturo
Published: August 2018

Cryptococcus neoformansis a pathogenic yeast capable of a unique and intriguing form of cell-to-cell transfer between macrophage cells. The mechanism for cell-to-cell transfer is not understood. Here we imaged macrophages with CellTracker Green CMFDA-labeled cytosol to ascertain whether cytosol was shared between donor and acceptor macrophages. Analysis of several transfer events detected no transfer of cytosol from donor to acceptor macrophages. However, blocking Fc and complement receptors resulted in a major diminution of cell-to-cell transfer events. The timing cell-to-cell transfer (11.17 min) closely approximated the sum of phagocytosis (4.18 min) and exocytosis (6.71 min) times. We propose that macrophage cell-to-cell transfer represents a non-lytic exocytosis event followed by phagocytosis into a macrophage that is in close proximity and name this process Dragotcytosis (Dragot is a Greek surname meaning ‘Sentinel’) as it represents sharing of a microbe between two sentinel cells of the innate immune system.
Superior dispersal ability leads to persistent ecological dominance by Candida pseudoglaebosa in the Sarracenia purpurea metacommunity
Authors: Boynton Primrose J. , Peterson Celeste N. , Pringle Anne
Published: August 2018

A large number of descriptive surveys document changes in microbial communities over time, but direct evidence for the ecological processes mediating succession or causing ecological dominance remains rare. Differential dispersal may be a key mechanism. We surveyed microbial diversity within a metacommunity of pitchers of the model carnivorous plant Sarracenia purpurea and discovered the yeast Candida pseudoglaebosa as ecologically dominant. Its frequency in the metacommunity increased over the growing season, and it was not replaced by other taxa. We next measured its competitive ability in a manipulative laboratory experiment and tracked its dispersal over time in nature. Despite its dominance, C. pseudoglaebosa is not a superior competitor. Instead, it is a superior disperser: it arrives in pitchers earlier, and disperses into more pitchers, than other taxa. Differential dispersal across the spatially structured metacommunity of individual pitchers emerges as a key driver of the continuous dominance of C. pseudoglaebosa during succession.
A conserved role of the insulin-like signaling pathway in uric acid pathologies revealed in Drosophila melanogaster
Authors: Lang Sven , Bose Neelanjan , Wilson Kenneth A. , Brackman Deanna J. , Hilsabeck Tyler , Watson Mark , Beck Jennifer N. , Sharma Amit , Chen Ling , Killilea David W. , Ho Sunita , Kahn Arnold , Giacomini Kathleen , Stoller Marshall L. , Chi Thomas , Kapahi Pankaj
Published: August 2018

Elevated uric acid (UA) is a key factor for disorders, including gout or kidney stones and result from abrogated expression of Urate Oxidase (Uro) and diet. To understand the genetic pathways influencing UA metabolism we established a Drosophila melanogaster model with elevated UA using Uro knockdown. Reduced Uro expression resulted in the accumulation of UA concretions and diet-dependent shortening of lifespan. Inhibition of insulin-like signaling (ILS) pathway genes reduced UA and concretion load. In humans, SNPs in the ILS genes AKT2 and FOXO3 were associated with UA levels or gout, supporting a conserved role for ILS in modulating UA metabolism. Downstream of the ILS pathway UA pathogenicity was mediated partly by NADPH Oxidase, whose inhibition attenuated the reduced lifespan and concretion accumulation. Thus, genes in the ILS pathway represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones.

Highlights

In Drosophila high uric acid (UA) levels shorten lifespan and cause UA aggregation

Conserved in flies and humans, the ILS pathway associates with UA pathologies

FoxO dampens concretion formation by reducing UA levels and ROS formation

Inhibition of NOX alleviates the lifespan attenuation and UA aggregation
Evaluation of a Dual Isolation Width Acquisition (DIWA) method for isobaric labelling ratio decompression
Authors: Roumeliotis Theodoros I. , Weisser Hendrik , Choudhary Jyoti S.
Published: August 2018

ABSRACT

Isobaric labelling is a highly precise approach for protein quantification. However, due to the isolation interference problem, isobaric tagging suffers from ratio underestimation at the MS2 level. The use of narrow isolation widths is a rational approach to alleviate the interference problem; however, this approach compromises proteome coverage. We reasoned that although a very narrow isolation window will result in loss of peptide fragment ions, the reporter ion signals will be retained for a significant portion of the spectra. Based on this assumption we have designed a Dual Isolation Width Acquisition (DIWA) method, in which each precursor is first fragmented with HCD using a standard isolation width for peptide identification and preliminary quantification, followed by a second MS2 HCD scan using a much narrower isolation width for the acquisition of quantitative spectra with reduced interference. We leverage the quantification obtained by the “narrow” scans to build linear regression models and apply these to decompress the fold-changes measured at the “standard” scans. We evaluate the DIWA approach using a nested two species/gene knockout TMT-6plex experimental design and discuss the perspectives of this approach.
Atypical flexibility in dynamic functional connectivity quantifies the severity in autism spectrum disorder
Authors: Harlalka Vatika , Bapi Raju S. , Vinod P.K. , Roy Dipanjan
Published: August 2018

Resting-state functional connectivity (FC) analyses have shown atypical connectivity in autism spectrum disorder (ASD) as compared to typically developing (TD). However, this view emerges from investigating static FC overlooking the age, disease phenotype and their interaction in the whole brain transient connectivity patterns. Contrasting with most extant literature in the present study, we investigated precisely how age and disease phenotypes factors into dynamic changes in functional connectivity of TD and ASD using resting-state functional magnetic resonance imaging (rs-fMRI) data stratified into three cohorts: children (7–11 years) and adolescents (12–17 years), and adults (18+) for the analysis. The dynamic variability in the connection strength and the modular organization in terms of measures: flexibility, cohesion strength and disjointness were explored for each subject to characterize the differences between ASD and TD.

In ASD, we observed significantly higher inter-subject dynamic variability in connection strength as compared to TD. This hypervariability relates to the symptom severity in ASD. We found that whole-brain flexibility correlates with static modularity only in TD. Further, we observed a core-periphery organization in the resting-state, with Sensorimotor and Visual regions in the rigid core; and DMN and attention areas in the flexible periphery. TD also develops a more cohesive organization of sensorimotor areas. However, in ASD we found a strong positive correlation of symptom severity with the flexibility of rigid areas and with disjointness of sensorimotor areas. The regions of the brain showing the high predictive power of symptom severity were distributed across the cortex, with stronger bearings in the frontal, motor and occipital cortices. Our study demonstrates that the dynamic framework best characterizes the variability in ASD.