Spore-forming bacteria as pharmaceutical factories

Many Bacilli form dormant structures, spores, which routinely survive physical, chemical and biological challenge. How do spores encapsulate their contents, and could it be possible to mimic or adapt them to make better drug products? Key spore component 2,6-dipicolinic acid (DPA) is necessary for protein stability, but investigation of its role is confounded with that of water content. Tests replacing DPA with chemical analogues were not successful, but led to the novel approach of doping spores with extra DPA. Various Bacillus species, in the main B. subtilis and B. thuringiensis, have been engineered to produce, for the first time, fragments of a humanized monoclonal antibody: kindly provided by Medimmune. It is possible to produce antibodies inside the spore core. This work proposes for the first time that such therapeutic spores might lack an outer coat, and demonstrates that antibody production continues. It is understood they continue to resist most challenges including wet heat, which damages proteins, yet they become susceptible to lysozyme. Such spores, further developed to lyse in presence of intestinal, though not gastric fluid, may have use in oral delivery. Cry1Ac of B. thuringiensis offers an alternative; large protein crystals are produced during sporulation. Here, various fluorescent fusions that maintain fluorescence over months were developed and investigated in detail. For the first time, fluorescent antibody crystals were produced. In addition to drug delivery, these fusions offer a novel approach to crystallization of intransigent proteins, for structural studies. This work shows that it might be feasible to use spores as pharmaceutical formulations. A number of challenges remain: from fabrication, through limits of current good manufacturing practice, to engineering biology to protect the environment and commercial interests. Bacterial spores have for the past century and a half been known for their dormancy, and it’s about time engineers took advantage.Medimmune (now AZ's biologics division) part funded the studentship and lab costs. Reference MA-417339

Private or Public Right? Who Should Adjudicate Patentability Disputes and Is the Current Scheme Really Constitutional?

“The patent bargain is the foundation upon which the patent system is built: in exchange for protections for an invention, the inventor agrees to make public their inventions so that others may build upon it.” The patent bargain creates a presumption of protection for the inventors, yet categorizing the patent a public right or a private right has diminished expectations for inventors and confusion for the masses. On October 11, 2016, the Supreme Court denied two petitions for writ of certiorari that challenged the constitutionality of Patent Trial and Review Board proceedings on the basis of the patent owner’s Seventh Amendment right to a jury trial and Article III separation of powers. The latter of those cases is the cornerstone for which this comment rests. In Cooper v. Lee, Petitioner J. Carl Cooper asked the United States Supreme Court to review a section of the Leahy-Smith America Invents Act that established “inter partes review,” (IPR) a procedure for administrative review of a patent. Making a number of constitutional challenges, Cooper asserts that inter partes review empowers an executive agency tribunal to assert judicial power cancelling a private property right. Moreover, Cooper stresses that patent disputes among private parties are disputes that have been known in the common law courts of 1789, afforded a trial, and cannot be adjudicated by an advisory opinion.6 After a tumultuous trip through the legal system in an attempt to finally determine the constitutionality of the IPR system, the high court has again left us pondering the issue of patent adjudication. With its denial of the petitioner’s writ for certiorari, the Court has again refused to declare whether patent rights are a private or public right. What does this mean for patent owners going forward? The waters are murky, but we will continue to see the adjudication of patent disputes by a non-Article III tribunal. This Comment examines a key question for patent administrative law: whether the grant of a patent is a public right, (i.e. a right that is primarily a concern of the public and can only be conferred by the government) thus subject to revocation by an administrative agency? In analyzing this concern, this Comment will address three subjects. First, this Comment will explore how section 311 of the Patent Act established the process of inter-partes proceedings and section 321 established the post-grant review of patents. Second, this Comment will outline the case law challenging the constitutionality of section 311 and section 321. Third, this Comment will examine the competing perspectives of whether a patent is a public or private right. This Comment has important implications for whether section 311 and section 321 are constitutional exercises of congressional power. Finally, this Comment will attempt to foreshadow how the outcome of current case law will affect the patent bargain and adjudication scheme

Local Rules and Procedures of the United States Court of Appeals for the Federal Circuit

The Federal Courts Improvement Act of 1982 abolished the United States Court of Claims and the United States Court of Customs and Patent Appeals and created the United States Court of Appeals for the Federal Circuit (CAFC) and the United States Claims Court. The Act provided for an advisory committee to be appointed by the CAFC in order to study the proposed rules of practice and internal operating procedures of the court. The recommendations of the advisory committee were given considerable weight when the court promulgated the Rules of the United States Court of Appeals for the Federal Circuit (CAFC Rules), and a procedural handbook effective October 1, 1982. The rules are intended to supplement the Federal Rules of Appellate Procedure and to reflect the court\u27s nationwide and varied jurisdiction, as well as a commitment to the expeditious determination of cases brought before it. This Article walks through the more pertinent rules which help to illustrate how the court will operate, as well as clarify earlier points of confusion

Rapid-Onset Anti-Stress Effects of a Kappa-Opioid Receptor Antagonist, LY2795050, against Immobility in an Open Space Swim Paradigm in Male and Female Mice

The kappa-opioid receptor (KOR) / dynorphin system is implicated with behavioral and neurobiological effects of stress exposure (including heavy exposure to drugs of abuse) in translational animal models. Thus some KOR-antagonists can decrease the aversive, depressant-like and anxiety-like effects caused by stress exposure. The first generation of selective KOR-antagonists have slow onsets (hours) and extremely long durations of action (days-weeks), in vivo. A new generation of KOR antagonists with rapid onset and shorter duration of action can potentially decrease the effects of stress exposure in translational models, and may be of interest for medication development. This study examined the rapid onset anti-stress effects of one of the shorter acting novel KOR-antagonists (LY2795050, (3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)) in a single-session open space swim (OSS) stress paradigm (15 min duration), in adult male and female C57BL/6 J mice. LY2795050 (0.32 mg/kg, i.p.) had rapid onset (within 15 min) and short duration (\u3c 3 h) of KOR-antagonist effects, based on its blockade of the locomotor depressant effects of the KOR-agonist U50,488 (10 mg/kg). LY2795050 (0.32 mg/kg), when administered only 1 min prior to the OSS stress paradigm, decreased immobility in males, but not females. With a slightly longer pretreatment time (15 min), this dose of LY2795050 decreased immobility in both males and females. A 10-fold smaller dose of LY2795050 (0.032 mg/kg) was inactive in the OSS, showing dose-dependence of this anti-stress effect. Overall, these studies show that a novel KOR-antagonist can produce very rapid onset anti-immobility effects in this model of acute stress exposure

Pilgrimage Project

The University of North Florida Pilgrimage Project combines interdisciplinary approaches with digital and STEM technologies and applies them to the study of pilgrimage with a special focus on the Camino de Santiago

Plato\u27s Villains: The Ethical Implications of Plato\u27s Portrayal of Alcibiades and Critias

Plato presents Socrates as an ethical example and a political warning. Other characters serve other philosophical functions. Alcibiades--the worst man in the democracy--and Critias--the worst in the oligarchy--are the most notorious characters.. This dissertation argues that Plato uses these characters in order to open a diachronic dimension in the synchronic accounts of the dialogues. This dimension turns historical characters into paradigmatic characters and allows the reader to evaluate the accounts people give in terms of the lives that they lead. In order to make a case for philosophy, Plato needs to make it clear that bad accounts have negative ethical effects, particularly over a period of time. The use of paradigmatic characters like Alcibiades and Critias allows him to make this case in the strongest possible way, while also allowing him to explore the relationship between time and virtue. I show that the connection between time and virtue explains not only individual decline, but also the historical decline described in Republic VIII. I offer close readings of the Protagoras, the Alcibiades I, the Symposium, the Timaeus-Critias, the Charmides and the Republic in order to show Plato\u27s creation and use of the diachronic dimension surrounding paradigmatic characters in order to show the effects of time on virtue. In so doing, I substantially contribute to our understanding of (1) Plato\u27s use of historical characters; (2) his understanding of the human experience of time; and (3) the nature of Socratic intellectualism and its relationship to error. I show that Socrates uses elenctic questioning in order to avoid the self-forgetfulness in the face of time that allowed both Alcibiades and Critias to become so vicious, even while intending to do the good