Swarm behavior of self-propelled rods and swimming flagella

Systems of self-propelled particles are known for their tendency to aggregate and to display swarm behavior. We investigate two model systems, self-propelled rods interacting via volume exclusion, and sinusoidally-beating flagella embedded in a fluid with hydrodynamic interactions. In the flagella system, beating frequencies are Gaussian distributed with a non-zero average. These systems are studied by Brownian-dynamics simulations and by mesoscale hydrodynamics simulations, respectively. The clustering behavior is analyzed as the particle density and the environmental or internal noise are varied. By distinguishing three types of cluster-size probability density functions, we obtain a phase diagram of different swarm behaviors. The properties of clusters, such as their configuration, lifetime and average size are analyzed. We find that the swarm behavior of the two systems, characterized by several effective power laws, is very similar. However, a more careful analysis reveals several differences. Clusters of self-propelled rods form due to partially blocked forward motion, and are therefore typically wedge-shaped. At higher rod density and low noise, a giant mobile cluster appears, in which most rods are mostly oriented towards the center. In contrast, flagella become hydrodynamically synchronized and attract each other; their clusters are therefore more elongated. Furthermore, the lifetime of flagella clusters decays more quickly with cluster size than of rod clusters

A molecular basis of analgesic tolerance to cannabinoids

Clinical usage of cannabinoids in chronic pain states is limited by their central side effects and the pharmacodynamic tolerance that sets in after repeated dosage. Analgesic tolerance to cannabinoids in vivo could be caused by agonist-induced downregulation and intracellular trafficking of cannabinoid receptors, but little is known about the molecular mechanisms involved. We show here that the type 1 cannabinoid receptor (CB1) interacts physically with G-protein-associated sorting protein 1 (GASP1), a protein that sorts receptors in lysosomal compartments destined for degradation. CB1 - GASP1 interaction was observed to be required for agonist-induced downregulation of CB1 in spinal neurons ex vivo as well as in vivo. Importantly, uncoupling CB1 from GASP1 in mice in vivo abrogated tolerance toward cannabinoid-induced analgesia. These results suggest that GASP1 is a key regulator of the fate of CB1 after agonist exposure in the nervous system and critically determines analgesic tolerance to cannabinoids

Mechanisms of Compartmentalized Expression of Mrg Class G-Protein-Coupled Sensory Receptors

Mrg class G-protein-coupled receptors (GPCRs) are expressed exclusively in sensory neurons in the trigeminal and dorsal root ganglia. Pharmacological activation of Mrg proteins is capable of modulating sensory neuron activities and elicits nociceptive effects. In this study, we illustrate a control mechanism that allows the Runx1 runt domain transcription factor to generate compartmentalized expression of these sensory GPCRs. Expression of MrgA, MrgB, and MrgC subclasses is confined to an “A/B/C” neuronal compartment that expresses Runx1 transiently (or does not express Runx1), whereas MrgD expression is restricted to a “D” compartment with persistent Runx1 expression. Runx1 is initially required for the expression of all Mrg genes. However, during late development Runx1 becomes a repressor for MrgA/B/C genes. As a result, MrgA/B/C expression persists only in the Runx1^− “A/B/C” compartment. In Δ446 mice, in which Runx1 lacks the C-terminal repression domain, expression of MrgA/B/C genes is dramatically expanded into the Runx1^+ “D” compartment. MrgD expression, however, is resistant to Runx1-mediated repression in the “D” compartment. Therefore, the creation of Runx1+ and Runx1^− compartments, in conjunction with different responses of Mrg genes to Runx1-mediated repression, results in the compartmentalized expression of MrgA/B/C versus MrgD genes. Within the MrgA/B/C compartment, MrgB4-expressing neurons innervate exclusively the hairy skin. Here we found that Smad4, a downstream component of bone morphological protein-mediated signaling, is required selectively for the expression of MrgB4. Our study suggests a new line of evidence that specification of sensory subtypes is established progressively during perinatal and postnatal development

Fatty acid modulation and polyamine block of GluK2 kainate receptors analyzed by scanning mutagenesis

RNA editing of kainate receptor subunits at the Q/R site determines their susceptibility to inhibition by cis-unsaturated fatty acids as well as block by cytoplasmic polyamines. Channels comprised of unedited (Q) subunits are strongly blocked by polyamines, but insensitive to fatty acids, such as arachidonic acid (AA) and docosahexaenoic acid (DHA), whereas homomeric edited (R) channels resist polyamine block but are inhibited by AA and DHA. In the present study, we have analyzed fatty acid modulation of whole-cell currents mediated by homomeric recombinant GluK2 (formerly GluR6) channels with individual residues in the pore-loop, M1 and M3 transmembrane helices replaced by scanning mutagenesis. Our results define three abutting surfaces along the M1, M2, and M3 helices where gain-of-function substitutions render GluK2(Q) channels susceptible to fatty acid inhibition. In addition, we identify four locations in the M3 helix (F611, L614, S618, and T621) at the level of the central cavity where Arg substitution increases relative permeability to chloride and eliminates polyamine block. Remarkably, for two of these positions, L614R and S618R, exposure to fatty acids reduces the apparent chloride permeability and potentiates whole-cell currents ∼5 and 2.5-fold, respectively. Together, our results suggest that AA and DHA alter the orientation of M3 in the open state, depending on contacts at the interface between M1, M2, and M3. Moreover, our results demonstrate the importance of side chains within the central cavity in determining ionic selectivity and block by cytoplasmic polyamines despite the inverted orientation of GluK2 as compared with potassium channels and other pore-loop family members

Cirurgia de catarata em cães: observações trans e pós-operatórias em 10 casos

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Introduction: Institutionalisation beyond the nation state: new paradigms? Transatlantic relations: data, privacy and trade law

The chapter explores how we should understand the development of institutionalisation beyond the Nation State. It focuses largely but not exclusively upon a possibly ‘hard case’ of global governance, EU-US relations, long understood to be a non-institutionalised space, in light of recent legal and political developments in trade and data law How should we reflect upon ‘progress’ as a narrative beyond the Nation State? What is the place of bottom-up led process? The lexicon and framework of institutionalisation is argued to be both important and a valuable one worthy of being developed out of the shadows of many disciplines. Institutionalisation may be the antithesis of the desired political outcome and simultaneously also the panacea for all harms. Contrariwise, it is a highly provocative lexicon in its own right for its capacity to provoke questions of sovereignty and sensitivity towards embedded institutionalised frameworks. Transatlantic relations provide a vivid multi-disciplinary example of the relationship between institutionalisation and private power and quest for new forms of institutionalisation across a range of subjects. Exploring ‘de-institutionalisation’ may not capture adequately developments taking place between the EU and US in trade and data privacy. A broader context of extreme volatility in the global legal order is arguably also difficult to capture and pin down as to its specific temporal or conceptual elements. Strong internationalised institutionalisation appears to constitute the outcome of the ‘trade’ case study whereas weak localised institutionalisation appears to constitute the outcome of the ‘data’ case study. Nonetheless, they both represent important evolving concepts of power, rights and authority beyond the State

Neuropathic pain caused by miswiring and abnormal end organ targeting

Nerve injury leads to chronic pain and exaggerated sensitivity to gentle touch (allodynia) as well as a loss of sensation in the areas in which injured and non-injured nerves come together1-3. The mechanisms that disambiguate these mixed and paradoxical symptoms are unknown. Here we longitudinally and non-invasively imaged genetically labelled populations of fibres that sense noxious stimuli (nociceptors) and gentle touch (low-threshold afferents) peripherally in the skin for longer than 10 months after nerve injury, while simultaneously tracking pain-related behaviour in the same mice. Fully denervated areas of skin initially lost sensation, gradually recovered normal sensitivity and developed marked allodynia and aversion to gentle touch several months after injury. This reinnervation-induced neuropathic pain involved nociceptors that sprouted into denervated territories precisely reproducing the initial pattern of innervation, were guided by blood vessels and showed irregular terminal connectivity in the skin and lowered activation thresholds mimicking low-threshold afferents. By contrast, low-threshold afferents-which normally mediate touch sensation as well as allodynia in intact nerve territories after injury4-7-did not reinnervate, leading to an aberrant innervation of tactile end organs such as Meissner corpuscles with nociceptors alone. Genetic ablation of nociceptors fully abrogated reinnervation allodynia. Our results thus reveal the emergence of a form of chronic neuropathic pain that is driven by structural plasticity, abnormal terminal connectivity and malfunction of nociceptors during reinnervation, and provide a mechanistic framework for the paradoxical sensory manifestations that are observed clinically and can impose a heavy burden on patients.The research leading to these results has received funding from the following sources: an ERC Advanced Investigator grant to R.K. (Pain Plasticity 294293); grants from the Deutsche Forschungsgemeinschaft to R.K. (SFB1158, projects B01, B06), to T.K. (SFB1158, project B08), to S.G.L. (SFB1158, project A01) and to V.G. (SFB1158, project A03); a grant to B.O. (project number 371923335); and grant CIDEGENT/2020/052 from Generalitat Valenciana to F.J.T. R.K. is a member of the Molecular Medicine Partnership Unit of the European Molecular Biology Laboratory and Medical Faculty Heidelberg. V.G. and T.A.N. were partially supported by a post-doctoral fellowship and physician scientist fellowship, respectively, from the Medical Faculty Heidelberg. D.M. was partially supported by a post-doctoral fellowship from Excellence Cluster CellNetworks. We acknowledge support from the Interdisciplinary Neurobehavioral Core (INBC) for the behavioural experiments, the data storage service SDS@hd and bwMLS&WISO HPC supported by the state of Baden-Württemberg and the German Research Foundation (DFG) through grants INST 35/1314-1 FUGG and INST 35/1134-1 FUGG, respectively.Peer reviewe

The EU as a Good Global Actor

This paper outlines an exploratory workshop at City Law School, City, University of London funded by HEIF/ ‘EUTIP’ Marie Skłodowska-Curie Innovative Training Network (ITN) on understanding of the EU as a Good Global Actor.1 The EU has as its mission to be a good global governance actor yet is continuously challenged in the world. As a global actor, the EU is both a weak and strong actor in a divergent range of global governance areas. It is not comparable to study the EU as a global trade actor for example to its efforts in human rights, data, cyber or the environment. EU international relations constitutes arguably a booming field of law where the EU appears often to be a victim of its own success. The range of the subjects and objects of EU law continues to expand and the EU is arguably increasingly a victim of its own success, increasingly taking decisions with impacts on third countries or parties, subjecting more entities to sanctions regimes, being bound to consult more entities and have more third countries, parties and entities such as lobbyists interested in the directions of EU law. The assessment of the EU as a global actor includes broad checks on normative action ex ante and ex post facto- yet it is no less harsh. Ex ante metrics of EU global action include court-centred ones such as an opinion from the CJEU on legality of an international agreement, often precluded in most constitutional systems on account of its conflict with pacta sunt servanda. The contours of the principle of the autonomy of EU law have the capacity to put more stringent parameters on EU institutionalised evolutions as to international engagement. How can we assess the EU as a global actor given these realities? The aim of the event was to explore informally the nexus between trade and security, trade and economics and trade and human rights as a future research agenda with input from a variety of scholars It reflected upon four major themes: 1) The EU’s Contribution to the Democratisation of Global Governance 2) Deeper Trade Agreements and New Normative Foundations 3) The EU as a Global Actor in Trade and Fundamental Rights 4) EU’s Trade in the Era of Global Data Flows