On Soliton Automorphisms in Massive and Conformal Theories

For massive and conformal quantum field theories in 1+1 dimensions with a global gauge group we consider soliton automorphisms, viz. automorphisms of the quasilocal algebra which act like two different global symmetry transformations on the left and right spacelike complements of a bounded region. We give a unified treatment by providing a necessary and sufficient condition for the existence and Poincare' covariance of soliton automorphisms which is applicable to a large class of theories. In particular, our construction applies to the QFT models with the local Fock property -- in which case the latter property is the only input from constructive QFT we need -- and to holomorphic conformal field theories. In conformal QFT soliton representations appear as twisted sectors, and in a subsequent paper our results will be used to give a rigorous analysis of the superselection structure of orbifolds of holomorphic theories.Comment: latex2e, 20 pages. Proof of Thm. 3.14 corrected, 2 references added. Final version as to appear in Rev. Math. Phy

Functional Consequences of Compartmentalization of Synaptic Input

Intra-axonal recordings of stomatogastric nerve axon 1 (SNAX1) indicate that there are synaptic inputs onto the SNAX1 terminals in the stomatogastric ganglion (STG) of the crab Cancer borealis (Nusbaum et al., 1992b). To determine whether this synaptic input only influenced SNAX1 activity within the STG, we identified the SNAX1 soma in the commissural ganglion (CoG). We found that this neuron has a neuropilar arborization in the CoG and also receives synaptic inputs in this ganglion. Based on its soma location, we have renamed this neuron modulatory commissural neuron 1 (MCN1). While intracellular stimulation of MCN1soma and MCN1SNAX has the same excitatory effects on the STG motor patterns, MCN1 receives distinct synaptic inputs in the STG and CoG. Moreover, the synaptic input that MCN1 receives within the STG compartmentalizes its activity. Specifically, the lateral gastric (LG) neuron synaptically inhibits MCN1SNAX-initiated activity within the STG (Nusbaum et al., 1992b), and while LG did not inhibit MCN1soma- initiated activity in the CoG, it did inhibit these MCN1 impulses when they arrived in the STG. As a result, during MCN1soma-elicited gastric mill rhythms, MCN1soma is continually active in the CoG but its effects are rhythmically inhibited in the STG by LG neuron impulse bursts. One functional consequence of this local control of MCN1 within the STG is that the LG neuron thereby controls the timing of the impulse bursts in other gastric mill neurons. Thus, local synaptic input can functionally compartmentalize the activity of a neuron with arbors in distinct regions of the nervous system

Lipopolysaccharide-induced neuroinflammation induces presynaptic disruption through a direct action on brain tissue involving microglia-derived interleukin 1 beta.

BACKGROUND: Systemic inflammation has been linked to synapse loss and cognitive decline in human patients and animal models. A role for microglial release of pro-inflammatory cytokines has been proposed based on in vivo and primary culture studies. However, mechanisms are hard to study in vivo as specific microglial ablation is challenging and the extracellular fluid cannot be sampled without invasive methods. Primary cultures have different limitations as the intricate multicellular architecture in the brain is not fully reproduced. It is essential to confirm proposed brain-specific mechanisms of inflammatory synapse loss directly in brain tissue. Organotypic hippocampal slice cultures (OHSCs) retain much of the in vivo neuronal architecture, synaptic connections and diversity of cell types whilst providing convenient access to manipulate and sample the culture medium and observe cellular reactions. METHODS: OHSCs were generated from P6-P9 C57BL/6 mice. Inflammation was induced via addition of lipopolysaccharide (LPS), and cultures were analysed for changes in synaptic proteins, gene expression and protein secretion. Microglia were selectively depleted using clodronate, and the effect of IL1β was assessed using a specific neutralising monoclonal antibody. RESULTS: LPS treatment induced loss of the presynaptic protein synaptophysin without altering PSD95 or Aβ protein levels. Depletion of microglia prior to LPS application prevented the loss of synaptophysin, whilst microglia depletion after the inflammatory insult was partially effective, although less so than pre-emptive treatment, indicating a time-critical window in which microglia can induce synaptic damage. IL1β protein and mRNA were increased after LPS addition, with these effects also prevented by microglia depletion. Direct application of IL1β to OHSCs resulted in synaptophysin loss whilst pre-treatment with IL1β neutralising antibody prior to LPS addition prevented a significant loss of synaptophysin but may also impact basal synaptic levels. CONCLUSIONS: The loss of synaptophysin in this system confirms LPS can act directly within brain tissue to disrupt synapses, and we show that microglia are the relevant cellular target when all major CNS cell types are present. By overcoming limitations of primary culture and in vivo work, our study strengthens the evidence for a key role of microglia-derived IL1β in synaptic dysfunction after inflammatory insult.Alzheimer’s Research UK project grant ARUK-PG2015-24 and The John and Lucille Van Geest Foundation

Traumatic Axonal Injury: Mechanisms and Translational Opportunities.

Traumatic axonal injury (TAI) is an important pathoanatomical subgroup of traumatic brain injury (TBI) and a major driver of mortality and functional impairment. Experimental models have provided insights into the effects of mechanical deformation on the neuronal cytoskeleton and the subsequent processes that drive axonal injury. There is also increasing recognition that axonal or white matter loss may progress for years post-injury and represent one mechanistic framework for progressive neurodegeneration after TBI. Previous trials of novel therapies have failed to make an impact on clinical outcome, in both TBI in general and TAI in particular. Recent advances in understanding the cellular and molecular mechanisms of injury have the potential to translate into novel therapeutic targets.CSH is supported by a Wellcome Trust PhD for Clinicians. MPC is funded by the John and Lucille van Geest Foundation. DKM is supported by a Senior Investigator Award from the National Institute for Health Research, UK (NIHR), by the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre, and a Framework Program 7 grant from the European Union (CENTER-TBI; Grant No: 602150)This is the final version of the article. It first appeared from Elsevier via https://doi.org/ 10.1016/j.tins.2016.03.00

The HSV-1 Latency-Associated Transcript Functions to Repress Latent Phase Lytic Gene Expression and Suppress Virus Reactivation from Latently Infected Neurons

open access articleHerpes simplex virus 1 (HSV-1) establishes life-long latent infection within sensory neurons, during which viral lytic gene expression is silenced. The only highly expressed viral gene product during latent infection is the latency-associated transcript (LAT), a non-protein coding RNA that has been strongly implicated in the epigenetic regulation of HSV-1 gene expression. We have investigated LAT-mediated control of latent gene expression using chromatin immunoprecipitation analyses and LAT-negative viruses engineered to express firefly luciferase or β-galactosidase from a heterologous lytic promoter. Whilst we were unable to determine a significant effect of LAT expression upon heterochromatin enrichment on latent HSV-1 genomes, we show that reporter gene expression from latent HSV-1 genomes occurs at a greater frequency in the absence of LAT. Furthermore, using luciferase reporter viruses we have observed that HSV-1 gene expression decreases during long-term latent infection, with a most marked effect during LAT-negative virus infection. Finally, using a fluorescent mouse model of infection to isolate and culture single latently infected neurons, we also show that reactivation occurs at a greater frequency from cultures harbouring LAT-negative HSV-1. Together, our data suggest that the HSV-1 LAT RNA represses HSV-1 gene expression in small populations of neurons within the mouse TG, a phenomenon that directly impacts upon the frequency of reactivation and the maintenance of the transcriptionally active latent reservoir

Neuropeptide Degradation Produces Functional Inactivation in the Crustacean Nervous System

The pentapeptide proctolin (Proct.; Arg-Tyr-Leu-Pro-Thr) is a modulatory transmitter found throughout the crustacean nervous system. No information is available in this system, however, as to how the actions of this peptide are terminated. To study this issue in the crab Cancer borealis, we incubated exogenous proctolin (10(-5) M) with either the thoracic ganglion (TG) or with conditioned saline (CS) that had been preincubated with the TG. We removed aliquots at standard time points for analysis by reverse-phase high-performance liquid chromatography (HPLC). We found that over time the proctolin peak became progressively smaller, while three novel peaks appeared and increased in size. Comigration experiments using HPLC indicated that the major novel peak was Proct. (Tyr-Leu-Pro-Thr), while one of the two minor peaks was Proct. (Leu-Pro-Thr). The other minor peak appeared to be Proct. (Arg-Tyr), based on similar HPLC retention time to synthetic Proct. The reduction in the proctolin peak and the increase in the Proct. peak was prevented by co-incubation of proctolin with any one of several aminopeptidase inhibitors (10(-4) M). Proct. and Proct. appeared to result from a diaminopeptidase-mediated cleavage of proctolin. We tested whether N-terminal cleavage functionally inactivated proctolin by coapplying proctolin (10(-8) M) and individual aminopeptidase inhibitors (10(-5) M) to the isolated stomatogastric ganglion (STG). We found that these inhibitors significantly enhanced the proctolin excitation of the pyloric rhythm. Furthermore, application of synthetic Proct. to the STG had no effect unless high concentrations (\u3e 10(-6) M) were used, and neither Proct. nor Proct. (10(-4) M) influenced the pyloric rhythm. Our results indicate that proctolin is enzymatically degraded and thereby biologically inactivated in the crab nervous system, primarily by extracellularly located aminopeptidase activity

Auxiliary master equation for nonequilibrium dual-fermion approach

We introduce auxiliary quantum master equation - dual fermion approach (QME-DF) and argue that it presents a convenient way to describe steady-states of correlated impurity systems. The combined scheme yields an expansion around a reference much closer to the true nonequilibrium state than in the original dual fermion formulation. In steady-state situations, the scheme is numerically cheaper and allows to avoid long time propagation of previous considerations. Anderson impurity is used as a test model. The QME-DF simulations are compared with numerically exact tdDMRG results.Comment: 8 pages, 4 figure

Intermediate Mass Black Hole Induced Quenching of Mass Segregation in Star Clusters

In many theoretical scenarios it is expected that intermediate-mass black holes (IMBHs, with masses M ~ 100-10000 solar masses) reside at the centers of some globular clusters. However, observational evidence for their existence is limited. Several previous numerical investigations have focused on the impact of an IMBH on the cluster dynamics or brightness profile. Here we instead present results from a large set of direct N-body simulations including single and binary stars. These show that there is a potentially more detectable IMBH signature, namely on the variation of the average stellar mass between the center and the half-light radius. We find that the existence of an IMBH quenches mass segregation and causes the average mass to exhibit only modest radial variation in collisionally relaxed star clusters. This differs from when there is no IMBH. To measure this observationally requires high resolution imaging at the level of that already available from the Hubble Space Telescope (HST) for the cores of a large sample of galactic globular clusters. With a modest additional investment of HST time to acquire fields around the half-light radius, it will be possible to identify the best candidate clusters to harbor an IMBH. This test can be applied only to globulars with a half-light relaxation time less than or equal to 1 Gyr, which is required to guarantee efficient energy equipartition due to two-body relaxation.Comment: 15 pages, 3 figures, ApJ, in pres

Short-term diabetic hyperglycemia suppresses celiac ganglia neurotransmission, thereby impairing sympathetically mediated glucagon responses.

Short-term hyperglycemia suppresses superior cervical ganglia neurotransmission. If this ganglionic dysfunction also occurs in the islet sympathetic pathway, sympathetically mediated glucagon responses could be impaired. Our objectives were 1) to test for a suppressive effect of 7 days of streptozotocin (STZ) diabetes on celiac ganglia (CG) activation and on neurotransmitter and glucagon responses to preganglionic nerve stimulation, 2) to isolate the defect in the islet sympathetic pathway to the CG itself, and 3) to test for a protective effect of the WLD(S) mutation. We injected saline or nicotine in nondiabetic and STZ-diabetic rats and measured fos mRNA levels in whole CG. We electrically stimulated the preganglionic or postganglionic nerve trunk of the CG in nondiabetic and STZ-diabetic rats and measured portal venous norepinephrine and glucagon responses. We repeated the nicotine and preganglionic nerve stimulation studies in nondiabetic and STZ-diabetic WLD(S) rats. In STZ-diabetic rats, the CG fos response to nicotine was suppressed, and the norepinephrine and glucagon responses to preganglionic nerve stimulation were impaired. In contrast, the norepinephrine and glucagon responses to postganglionic nerve stimulation were normal. The CG fos response to nicotine, and the norepinephrine and glucagon responses to preganglionic nerve stimulation, were normal in STZ-diabetic WLD(S) rats. In conclusion, short-term hyperglycemia's suppressive effect on nicotinic acetylcholine receptors of the CG impairs sympathetically mediated glucagon responses. WLD(S) rats are protected from this dysfunction. The implication is that this CG dysfunction may contribute to the impaired glucagon response to insulin-induced hypoglycemia seen early in type 1 diabetes

The axon-protective WLD(S) protein partially rescues mitochondrial respiration and glycolysis after axonal injury.

The axon-protective Wallerian degeneration slow (WLD(S)) protein can ameliorate the decline in axonal ATP levels after neurite transection. Here, we tested the hypothesis that this effect is associated with maintenance of mitochondrial respiration and/or glycolysis. We used isolated neurites of superior cervical ganglion (SCG) cultures in the Seahorse XF-24 Metabolic Flux Analyser to determine mitochondrial respiration and glycolysis under different conditions. We observed that both mitochondrial respiration and glycolysis declined significantly during the latent phase of Wallerian degeneration. WLD(S) partially reduced the decline both in glycolysis and in mitochondrial respiration. In addition, we found that depleting NAD levels in uncut cultures led to changes in mitochondrial respiration and glycolysis similar to those rescued by WLD(S) after cut, suggesting that the maintenance of NAD levels in Wld(S) neurites after axonal injury at least partially underlies the maintenance of ATP levels. However, by using another axon-protective mutation (Sarm1(-/-)), we could demonstrate that rescue of basal ECAR (and hence probably glycolysis) rather than basal OCR (mitochondrial respiration) may be part of the protective phenotype to delay Wallerian degeneration. These findings open new routes to study glycolysis and the connection between NAD and ATP levels in axon degeneration, which may help to eventually develop therapeutic strategies to treat neurodegenerative diseases