What’s So Special About Patent Law?

The widespread belief that patent law is special has shaped the development of patent law into one of the most specialized areas of the law today. The belief in patent law’s exceptionalism manifests itself as two related presumptions with respect to the judiciary: first, that generalist judges who do not have patent law expertise cannot effectively decide patent cases, and second, that judges can develop necessary expertise through repeated experience with patent cases. Congress showed that it acquiesced to both views when it created the Federal Circuit and the Patent Pilot Program. In recent years, however, the Supreme Court has reminded us that the judiciary’s difficulty with patent cases is not the law, but is instead that patent cases often involve difficult subject matter, which sometimes requires technical or scientific expertise. While Congress’s early attempts to deal with these difficulties focused on courts with legal―rather than technical―expertise, the Supreme Court’s recent pronouncements suggest that they should have been doing the reverse. Moreover, to the extent that it is the underlying technology that makes patent cases difficult, that commends the use of an administrative, rather than a judicial, solution. One potentially viable answer to the judiciary’s problem with patent law has already been partly implemented in the form of the recently created Patent Trial and Appeal Board. This Article proposes expansion of that solution by making that new entity the exclusive forum for deciding issues of patent validity

Protein kinase C epsilon controls metabotropic glutamate receptor 5 calcium signaling and its potential implication in amyotrophic lateral sclerosis

The metabotropic glutamate receptor 5 (mGluR5) represents the glutamate sensor of astrocytes and is thought to participate in the regulation of diverse astrocytic functions. The mGluR5 has the particularity to show distinct calcium patterns upon activation including sustained calcium mobilization or calcium oscillations. In our laboratory, we are convinced that these patterns differently impact on the mGluR5-mediated regulation of astrocytic functions. In this thesis, we highlight that mGluR5 activation associated with calcium oscillations protects against receptor desensitization while sustained calcium mobilization is associated with robust desensitization. In addition, we demonstrate that calcium oscillations induced by mGluR5 activation regulate the astrocytic glutamate transport while sustained calcium mobilization has no effect. We also add new insight into the role of PKC epsilon, by showing its implication in the regulation of mGluR5 calcium oscillations.(ART - Art et sciences de l'art) -- UCL, 201

Constitutive downregulation protein kinase C epsilon in hSOD1 astrocytes influences mGluR5 signaling and the regulation of glutamate uptake.

Accumulating evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is a non-cell-autonomous process and that impaired glutamate clearance by astrocytes, leading to excitotoxicity, could participate in progression of the disease. In astrocytes derived from an animal model of ALS (hSOD1 rats), activation of type 5 metabotropic glutamate receptor (mGluR5) fails to increase glutamate uptake, impeding a putative dynamic neuroprotective mechanism involving astrocytes. Using astrocyte cultures from hSOD1 rats, we have demonstrated that the typical Ca oscillations associated with mGluR5 activation were reduced, and that the majority of cells responded with a sustained elevation of intracellular Ca concentration. Since the expression of protein kinase C epsilon isoform (PKCɛ) has been found to be considerably reduced in astrocytes from hSOD1 rats, the consequences of manipulating its activity and expression on mGluR5 signaling and on the regulation of glutamate uptake have been examined. Increasing PKCɛ expression was found to restore Ca oscillations induced by mGluR5 activation in hSOD1 -expressing astrocytes. This was also associated with an increase in glutamate uptake capacity in response to mGluR5 activation. Conversely, reducing PKCɛ expression in astrocytes from wild-type animals with specific PKCɛ-shRNAs was found to alter the mGluR5 associated oscillatory signaling profile, and consistently reduced the regulation of the glutamate uptake-mediated by mGluR5 activation. These results suggest that PKCɛ is required to generate Ca oscillations following mGluR5 activation, which support the regulation of astrocytic glutamate uptake. Reduced expression of astrocytic PKCɛ could impair this neuroprotective process and participate in the progression of ALS

Immunomodulatory influence of bone marrow-derived mesenchymal stem cells on neuroinflammation in astrocyte cultures.

The therapeutic benefits associated with mesenchymal stem cells (MSCs) largely result from their immunomodulatory and neurotrophic properties. In this study, we evaluated the effects of MSCs on astrocyte cultures exposed to lipopolysaccharide. In response to this inflammatory trigger, astrocytes showed an increased expression of pro-inflammatory genes (IL-1β, TNFα, IL-6), which was attenuated by pre-exposure to MSC conditioned medium. Furthermore, mediators released by MSCs increased cell proliferation and altered the regulation of intermediate filaments (GFAP, vimentin), pro-inflammatory enzymes (iNOS, COX-2) and receptors (TLR4, CD14, mGluR3, mGluR5). These data demonstrate that MSCs influence diverse cell types participating in the response to neuroinflammation

PKC epsilon dependent calcium oscillations associated with metabotropic glutamate receptor 5 prevent agonist-mediated receptor desensitization in astrocytes.

A critical role has been assigned to PKCε in the control of intracellular calcium oscillations triggered upon activation of type 5 metabotropic glutamate receptor (mGluR5) in cultured astrocytes. Nevertheless, the physiological significance of this particular signalling profile in the response of astrocytes to glutamate remains largely unknown. Considering that kinases are frequently involved in the regulation of G-protein coupled receptors, we have examined a putative link between the nature of the calcium signals and the response regulation upon repeated exposures of astrocytes to the agonist (S)-3,5-dihydroxyphenylglycine. We show that upon repeated mGluR5 activations, a robust desensitization was observed in astrocytes grown in culture conditions favouring the peak-plateau type response. At variance, in cell cultures where calcium oscillations were predominating, the response was fully preserved even during repeated challenges with the agonist. Pharmacological inhibition of PKCε or genetic suppression of this isoform using shRNA was found to convert an oscillatory calcium profile to a sustained calcium mobilization and this latter profile was subject to desensitization upon repetitive mGluR5 activation. Our results suggest a yet undocumented scheme in which the activity of PKCε contributes to preserve the receptor sensitivity upon repeated or sustained activations. This article is protected by copyright. All rights reserved

The anti-inflammatory peptide stearyl-norleucine-VIP delays disease onset and extends survival in a rat model of inherited amyotrophic lateral sclerosis.

Vasoactive intestinal peptide (VIP) has potent immune modulatory actions that may influence the course of neurodegenerative disorders associated with chronic inflammation. Here, we show the therapeutic benefits of a modified peptide agonist stearyl-norleucine-VIP (SNV) in a transgenic rat model of amyotrophic lateral sclerosis (mutated superoxide dismutase 1, hSOD1(G93A)). When administered by systemic every-other-day intraperitoneal injections during a period of 80 days before disease, SNV delayed the onset of motor dysfunction by no less than three weeks, while survival was extended by nearly two months. SNV-treated rats showed reduced astro- and microgliosis in the lumbar ventral spinal cord and a significant degree of motor neuron preservation. Throughout the treatment, SNV promoted the expression of the anti-inflammatory cytokine interleukin-10 as well as neurotrophic factors commonly considered as beneficial in amyotrophic lateral sclerosis management (glial derived neuroptrophic factor, insulin like growth factor, brain derived neurotrophic factor). The peptide nearly totally suppressed the expression of tumor necrosis factor-α and repressed the production of the pro-inflammatory mediators interleukin-1β, nitric oxide and of the transcription factor nuclear factor kappa B. Inhibition of tumor necrosis factor-α likely accounted for the observed down-regulation of nuclear factor kappa B that modulates the transcription of genes specifically involved in amyotrophic lateral sclerosis (sod1 and the glutamate transporter slc1a2). In line with this, levels of human superoxide dismutase 1 mRNA and protein were decreased by SNV treatment, while the expression and activity of the glutamate transporter-1 was promoted. Considering the large diversity of influences of this peptide on both clinical features of the disease and associated biochemical markers, we propose that SNV or related peptides may constitute promising candidates for amyotrophic lateral sclerosis treatment

Opposite regulation of metabotropic glutamate receptor 3 and metabotropic glutamate receptor 5 by inflammatory stimuli in cultured microglia and astrocytes.

Metabotropic glutamate receptors (mGluRs) were previously shown to modulate several essential functions in glial cells, including cell proliferation, glutamate uptake, neurotrophic support, and inflammatory responses. As these receptors are regularly proposed as promising targets for the treatment of a wide range of neurological disorders, we herein examined the reciprocal modulation of glial mGluRs by inflammation. Such regulation of mGluRs was also studied in cultures from an experimental model of amyotrophic lateral sclerosis (ALS). Indeed, ALS is characterized by increased neuroinflammation, and glial cell cultures derived from the animal model (rat expressing hSOD1(G93A)) show enhanced glial reactivity. Within 72 h, the pro-inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin 1β (IL-1β) induced an increase in mGluR3 and a decrease in mGluR5 gene expression. A similar regulation of these receptors was observed in microglia 48 h after an initial 4-h exposure to lipopolysaccharide. In hSOD1(G93A)-derived glial cultures, the gene up-regulation of mGluR3 (but not the gene down-regulation of mGluR5) was found to be enhanced in both astrocytes and microglia. Together, these results indicate that an inflammatory environment triggers an opposite regulation in the gene expression of the two predominant mGluR subtypes found in glial cells, and that these regulations were particularly robust in hSOD1(G93A) glial cultures. As neuroinflammation commonly occurs in several nervous diseases, its influence on mGluR expression should be taken into account when considering these receptors as future drug targets

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release.

The amyloid precursor protein (APP) has been extensively studied as the precursor of the β-amyloid (Aβ) peptide, the major component of the senile plaques found in the brain of Alzheimer's disease (AD) patients. However, the function of APP per se in neuronal physiology remains to be fully elucidated. APP is expressed at high levels in the brain. It resembles a cell adhesion molecule or a membrane receptor, suggesting that its function relies on cell-cell interaction and/or activation of intracellular signaling pathways. In this respect, the APP intracellular domain (AICD) was reported to act as a transcriptional regulator. Here, we used a transcriptome-based approach to identify the genes transcriptionally regulated by APP in the rodent embryonic cortex and on maturation of primary cortical neurons. Surprisingly, the overall transcriptional changes were subtle, but a more detailed analysis pointed to genes clustered in neuronal-activity dependent pathways. In particular, we observed a decreased transcription of neuronal PAS domain protein 4 (NPAS4) in APP-/- neurons. NPAS4 is an inducible transcription factor (ITF) regulated by neuronal depolarization. The downregulation of NPAS4 co-occurs with an increased production of the inhibitory neurotransmitter GABA and a reduced expression of the GABA receptors α1. CRISPR-Cas-mediated silencing of NPAS4 in neurons led to similar observations. Patch-clamp investigation did not reveal any functional decrease of GABA receptors activity, but long-term potentiation (LTP) measurement supported an increased GABA component in synaptic transmission of APP-/- mice. Together, NPAS4 appears to be a downstream target involved in APP-dependent regulation of inhibitory synaptic transmission