Compiler-Assisted Signature Monitoring

Coordinated Science Laboratory was formerly known as Control Systems LaboratoryJoint Services Electronics Program / N00014-84-C-0149Office of Naval Research / N00014-88-K-0656National Science Foundation / MIP-8809478NCRNational Aeronautics and Space Administration / NASA NAG 1-61

Gerstmann-Straussler-Scheinker disease in an Alsatian family: clinical and genetic studies

The clinical progression of Gerstmann-Straussler-Scheinker disease in a family of Alsatian origin is reported. The age of onset and the duration of evolution were variable. The clinical picture became more complex over the generations: in the first generations, isolated dementia and in later generations a triad of pyramidal, pseudobulbar syndromes and dementia associated with spinal cord and cerebellar features. Prion gene analysis showed that four surviving patients carry double missense changes at codons 117 and 129, identical to those found in one case at necropsy and 10 other healthy members of the family. The missense changes were not found in 100 controls. No member of the family had modification of condons 102, 178, or 200. The lod score suggests linkage between the missense change at codon 117 and Gerstmann- Straussler-Scheinker disease in this family

Childhood tetanus in Australia: ethical issues for a should-be-forgotten preventable disease

The document attached has been archived with permission from the editor of the Medical Journal of Australia. An external link to the publisher’s copy is included.Refusal of a parent to have a child vaccinated against tetanus raised ethical issues for the treating clinicians. The clinicians felt their duty to the child was compromised, but recognised that our society leaves the authority for such decisions with the parents. As there was no reason, other than different beliefs about vaccination, to doubt the parent's care for the child, the clinicians limited their response to providing strong recommendations in favour of vaccination. Other issues raised by this case include community protection, and the costs to the community of treating a vaccine-preventable disease.Paul N Goldwater, Annette J Braunack-Mayer, Richard G Power, Paul H Henning, Mike S Gold, Terence G Donald, Jon N Jureidini and Christine F Finla

Chikungunya Virus Neutralization Antigens and Direct Cell-to-Cell Transmission Are Revealed by Human Antibody-Escape Mutants

Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics throughout Africa and Asia, causing infectious arthritis and reportedly linked with fatal infections in newborns and elderly. Previous studies in animal models indicate that humoral immunity can protect against CHIKV infection, but despite the potential efficacy of B-cell-driven intervention strategies, there are no virus-specific vaccines or therapies currently available. In addition, CHIKV has been reported to elicit long-lasting virus-specific IgM in humans, and to establish long-term persistence in non-human primates, suggesting that the virus might evade immune defenses to establish chronic infections in man. However, the mechanisms of immune evasion potentially employed by CHIKV remain uncharacterized. We previously described two human monoclonal antibodies that potently neutralize CHIKV infection. In the current report, we have characterized CHIKV mutants that escape antibody-dependent neutralization to identify the CHIKV E2 domain B and fusion loop “groove” as the primary determinants of CHIKV interaction with these antibodies. Furthermore, for the first time, we have also demonstrated direct CHIKV cell-to-cell transmission, as a mechanism that involves the E2 domain A and that is associated with viral resistance to antibody-dependent neutralization. Identification of CHIKV sub-domains that are associated with human protective immunity, will pave the way for the development of CHIKV-specific sub-domain vaccination strategies. Moreover, the clear demonstration of CHIKV cell-to-cell transmission and its possible role in the establishment of CHIKV persistence, will also inform the development of future anti-viral interventions. These data shed new light on CHIKV-host interactions that will help to combat human CHIKV infection and inform future studies of CHIKV pathogenesis

Comparing chromosomal and mitochondrial phylogenies of the Indriidae (Primates, Lemuriformes)

The Malagasy primate family Indriidae comprises three genera with up to 19 species. Cytogenetic and molecular phylogenies of the Indriidae have been performed with special attention to the genus Propithecus. Comparative R-banding and FISH with human paints were applied to karyotypes of representatives of all three genera and confirmed most of the earlier R-banding results. However, additional chromosomal rearrangements were detected. A reticulated and a cladistic phylogeny, the latter including hemiplasies, have been performed. Cladistic analysis of cytogenetic data resulted in a phylogenetic tree revealing (1) monophyly of the family Indriidae, (2) monophyly of the genus Avahi, (3) sister–group relationships between Propithecus diadema and Propithecus edwardsi, and (4) the grouping of the latter with Indri indri, Propithecus verreauxi, and Propithecus tattersalli, and thus suggesting paraphyly of the genus Propithecus. A molecular phylogeny based on complete mitochondrial cytochrome b sequences of 16 species indicated some identical relationships, such as the monophyly of Avahi and the sister–group relationships of the eastern (P. diadema and P. edwardsi) to the western Propithecus species (P. verreauxi, Propithecus coquereli, and P. tattersalli). However, the main difference between the molecular and cytogenetic phylogenies consists in an early divergence of Indri in the molecular phylogeny while in the chromosomal phylogeny it is nested within Propithecus. The similarities and differences between molecular and cytogenetic phylogenies in relation to data on the species’ geographic distributions and mating systems allow us to propose a scenario of the evolution of Indriidae. Chromosomal and molecular processes alone or in combination created a reproductive barrier that was then followed by further speciation processes

Development of a highly protective combination monoclonal antibody therapy against Chikungunya virus

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar−/−) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans

Diagnostically Challenging Epithelial Odontogenic Tumors: A Selective Review of 7 Jawbone Lesions

Considerable variation in the clinicopathologic presentation of epithelial odontogenic tumors can sometimes be confusing and increase the chance of misdiagnosis. Seven diagnostically challenging jawbone lesions are described. There were 2 cases of mistaken identity in our ameloblastoma file. One unicystic type, initially diagnosed and treated as a lateral periodontal cyst, showed destructive recurrence 6 years postoperatively. The other globulomaxillary lesion was managed under the erroneous diagnosis of adenomatoid odontogenic tumor and recurred 4 times over an 11-year period. This tumor was found in retrospect to be consistent with an adenoid ameloblastoma with dentinoid. The diagnosis of cystic squamous odontogenic tumor (SOT) occurring as a radicular lesion of an impacted lower third molar was one of exclusion. Of two unsuspected keratocystic odontogenic tumors, one depicted deceptive features of pericoronitis, while the other case has long been in our files with the diagnosis of globulomaxillary SOT. Two cases of primary intraosseous squamous cell carcinoma appeared benign clinically and exhibited unexpected findings; an impacted third molar began to erupt in association with the growth of carcinoma and another periradicular carcinoma showed dentinoid formation. Cases selectively reviewed in this article present challenging problems which require clinical and radiographic correlation to avoid potential diagnostic pitfalls

A Cooperative Interaction between Nontranslated RNA Sequences and NS5A Protein Promotes In Vivo Fitness of a Chimeric Hepatitis C/GB Virus B

GB virus B (GBV-B) is closely related to hepatitis C virus (HCV), infects small non-human primates, and is thus a valuable surrogate for studying HCV. Despite significant differences, the 5′ nontranslated RNAs (NTRs) of these viruses fold into four similar structured domains (I-IV), with domains II-III-IV comprising the viral internal ribosomal entry site (IRES). We previously reported the in vivo rescue of a chimeric GBV-B (vGB/IIIHC) containing HCV sequence in domain III, an essential segment of the IRES. We show here that three mutations identified within the vGB/IIIHC genome (within the 3′NTR, upstream of the poly(U) tract, and NS5A coding sequence) are necessary and sufficient for production of this chimeric virus following intrahepatic inoculation of synthetic RNA in tamarins, and thus apparently compensate for the presence of HCV sequence in domain III. To assess the mechanism(s) underlying these compensatory mutations, and to determine whether 5′NTR subdomains participating in genome replication do so in a virus-specific fashion, we constructed and evaluated a series of chimeric subgenomic GBV-B replicons in which various 5′NTR subdomains were substituted with their HCV homologs. Domains I and II of the GBV-B 5′NTR could not be replaced with HCV sequence, indicating that they contain essential, virus-specific RNA replication elements. In contrast, domain III could be swapped with minimal loss of genome replication capacity in cell culture. The 3′NTR and NS5A mutations required for rescue of the related chimeric virus in vivo had no effect on replication of the subgenomic GBneoD/IIIHC RNA in vitro. The data suggest that in vivo fitness of the domain III chimeric virus is dependent on a cooperative interaction between the 5′NTR, 3′NTR and NS5A at a step in the viral life cycle subsequent to genome replication, most likely during particle assembly. Such a mechanism may be common to all hepaciviruses

Red Sea palaeoclimate: stable isotope and element-ratio analysis of marine mollusc shells

The southern Red Sea coast is the location of more than 4,200 archaeological shell midden sites. These shell middens preserve archaeological and climatic archives of unprecedented resolution and scale. By using shells from these contexts, it is possible to link past environmental information with episodes of human occupation and resource processing. This chapter summarises current knowledge about the marine gastropod Conomurex fasciatus (Born 1778) and discusses its use in environmental and climatic reconstruction using stable isotope and elemental ratio analysis. It offers a review of the most recent studies of shell midden sites on the Farasan Islands, their regional importance during the mid-Holocene, theories about seasonal use of the coastal landscape, and preliminary results from new methods to acquire large climatic datasets from C. fasciatus shells

Recombinant Modified Vaccinia Virus Ankara Expressing Glycoprotein E2 of Chikungunya Virus Protects AG129 Mice against Lethal Challenge

Chikungunya virus (CHIKV) infection is characterized by rash, acute high fever, chills, headache, nausea, photophobia, vomiting, and severe polyarthralgia. There is evidence that arthralgia can persist for years and result in long-term discomfort. Neurologic disease with fatal outcome has been documented, although at low incidences. The CHIKV RNA genome encodes five structural proteins (C, E1, E2, E3 and 6K). The E1 spike protein drives the fusion process within the cytoplasm, while the E2 protein is believed to interact with cellular receptors and therefore most probably constitutes the target of neutralizing antibodies. We have constructed recombinant Modified Vaccinia Ankara (MVA) expressing E3E2, 6KE1, or the entire CHIKV envelope polyprotein cassette E3E26KE1. MVA is an appropriate platform because of its demonstrated clinical safety and its suitability for expression of various heterologous proteins. After completing the immunization scheme, animals were challenged with CHIV-S27. Immunization of AG129 mice with MVAs expressing E2 or E3E26KE1 elicited neutralizing antibodies in all animals and provided 100% protection against lethal disease. In contrast, 75% of the animals immunized with 6KE1 were protected against lethal infection. In conclusion, MVA expressing the glycoprotein E2 of CHIKV represents as an immunogenic and effective candidate vaccine against CHIKV infections