Crime and Punishment in the Royal Navy: Discipline on the Leeward Islands Station, 1784-1812 (England).

This dissertation is based primarily on the manuscript sources pertaining to the Leeward Islands station between 1784 and 1812 found in the Public Record Office. Its thesis is quite simple: Discipline in the Royal Navy in the age of sail was maintained in much the same fashion that law and order was enforced in the localities of eighteenth-century England. In short, justice afloat was administered according to the principles and practices used in the system of criminal law ashore

Discovery of Novel, Orally Bioavailable β‑Amino Acid Azaindole Inhibitors of Influenza PB2

In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound <b>4</b>. Compound <b>4</b> showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound <b>4</b> offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza

Symmetry breaking: polymorphic form selection by enantiomers of the melatonin agonist and its missing polymorph

Synthesis of a melatonin agonist for treatment of sleep disorders produced a pair of enantiomers, of which one is biologically active. Two polymorphs were discovered using the inactive enantiomer, conserving the active enantiomer for toxicological testing. Later studies with the active enantiomer yielded only the metastable form, despite more than 1000 attempts to isolate the stable form. The difficulty is surprising, since the stable form is favored by 0.7 kcal mol–1, which is toward the extreme for stability differences between organic polymorphs. Study of individual enantiomers allowed the phase behavior of polymorphs of greatly different energy to be examined without interconversion. A number of unusual features are noted. After the stable polymorph of the inactive enantiomer was nucleated, the metastable form became very difficult to isolate. The metastable form converts into a less soluble monohydrate structure in water, whereas the stable polymorph does not due to its reduced activity. Both chiral polymorphs are denser than the racemic crystalline form at low temperature, the stable form being at the extreme for chiral-racemic pairs. Free energy-temperature relations predict “spontaneous resolution” of the racemic crystalline form into a conglomerate mixture of stable polymorph at low temperature. The unusual characteristics of the system are explained by hydrogen bonding and conformational flexibility of the molecule. Ab initio calculations aid in understanding the relative contributions of these interactions to the lattice energies and the role that conformational energy differences play in the polymorphic stability. This system highlights the importance of the creation of the very first nuclei of a crystalline form. The reluctance of the stable form to nucleate is attributed to a large energy difference between polymorphic forms. The large interfacial tension for primary nucleation reduces the probability of forming clusters of size sufficient for favorable growth in the absence of heterogeneous nucleation. This study highlights how nucleation of a new form can revise the readily “accessible” region of a compound’s crystal form landscape

Contribution of Immune Activation to the Pathogenesis and Transmission of Human Immunodeficiency Virus Type 1 Infection

The life cycle of human immunodeficiency virus type 1 (HIV-1) is intricately related to the activation state of the host cells supporting viral replication. Although cellular activation is essential to mount an effective host immune response to invading pathogens, paradoxically the marked systemic immune activation that accompanies HIV-1 infection in vivo may play an important role in sustaining phenomenal rates of HIV-1 replication in infected persons. Moreover, by inducing CD4(+) cell loss by apoptosis, immune activation may further be central to the increased rate of CD4(+) cell turnover and eventual development of CD4(+) lymphocytopenia. In addition to HIV-1-induced immune activation, exogenous immune stimuli such as opportunistic infections may further impact the rate of HIV-1 replication systemically or at localized anatomical sites. Such stimuli may also lead to genotypic and phenotypic changes in the virus pool. Together, these various immunological effects on the biology of HIV-1 may potentially enhance disease progression in HIV-infected persons and may ultimately outweigh the beneficial aspects of antiviral immune responses. This may be particularly important for those living in developing countries, where there is little or no access to antiretroviral drugs and where frequent exposure to pathogenic organisms sustains a chronically heightened state of immune activation. Moreover, immune activation associated with sexually transmitted diseases, chorioamnionitis, and mastitis may have important local effects on HIV-1 replication that may increase the risk of sexual or mother-to-child transmission of HIV-1. The aim of this paper is to provide a broad review of the interrelationship between immune activation and the immunopathogenesis, transmission, progression, and treatment of HIV-1 infection in vivo