Protection Afforded by an HIV Vaccine Candidate in Macaques Depends on the Dose of SIVmac251 at Challenge Exposure

We used the simian immunodeficiency virus mac251 (SIV_mac251) macaque model to study the effect of the dose of mucosal exposure on vaccine efficacy. We immunized macaques with a DNA prime followed by SIV gp120 protein immunization with ALVAC-SIV and gp120 in alum, and we challenged them with SIV_mac251 at either a single high dose or at two repeated low-dose exposures to a 10-fold-lower dose. Infection was neither prevented nor modified following a single high-dose challenge of the immunized macaques. However, two exposures to a 10-fold-lower dose resulted in protection from SIV_mac251 acquisition in 3 out of 12 macaques. The remaining animals that were infected had a modulated pathogenesis, significant downregulation of interferon responsive genes, and upregulation of genes involved in B- and T-cell responses. Thus, the choice of the experimental model greatly influences the vaccine efficacy of vaccines for human immunodeficiency virus (HIV).     

Modelling tropical fire ant (<Emphasis Type="Italic">Solenopsis geminata</Emphasis>) dynamics and detection to inform an eradication project

Invasive species threaten endangered species worldwide and substantial effort is focused on their control. Eradication projects require critical resource allocation decisions, as they affect both the likelihood of success and the overall cost. However, these complex decisions must often be made within data-poor environments. Here we develop a mathematical framework to assist in resource allocation for invasive species control projects and we apply it to the proposed eradication of the tropical fire ant (Solenopsis geminata) from the islands of Ashmore Reef in the Timor Sea. Our framework contains two models: a population model and a detection model. Our stochastic population model is used to predict ant abundance through time and allows us to estimate the probability of eradication. Using abundance predictions from the population model, we use the detection model to predict the probability of ant detection through time. These models inform key decisions throughout the project, which include deciding how many baiting events should take place, deciding whether to invest in detector dogs and setting surveillance effort to confirm eradication following control. We find that using a combination of insect growth regulator and toxins are required to achieve a high probability of eradication over 2 years, and we find that using two detector dogs may be more cost-effective than the use of lure deployment, provided that they are used across the life of the project. Our analysis lays a foundation for making decisions about control and detection throughout the project and provides specific advice about resource allocation.     

Molecular determinants of the aggregation behavior of alpha- and beta-synuclein

Alpha- and beta-synuclein are closely related proteins, the first of which is associated with deposits formed in neurodegenerative conditions such as Parkinson's disease while the second appears to have no relationship to any such disorders. The aggregation behavior of alpha- and beta-synuclein as well as a series of chimeric variants were compared by exploring the structural transitions that occur in the presence of a widely used lipid mimetic, sodium dodecyl sulfate (SDS). We found that the aggregation rates of all these protein variants are significantly enhanced by low concentrations of SDS. In particular, we inserted the 11-residue sequence of mainly hydrophobic residues from the non-amyloid-beta-component (NAC) region of alpha-synuclein into beta-synuclein and show that the fibril formation rate of this chimeric protein is only weakly altered from that of beta-synuclein. These intrinsic propensities to aggregate are rationalized to a very high degree of accuracy by analysis of the sequences in terms of their associated physicochemical properties. The results begin to reveal that the differences in behavior are primarily associated with a delicate balance between the positions of a range of charged and hydrophobic residues rather than the commonly assumed presence or absence of the highly aggregation-prone region of the NAC region of alpha-synuclein. This conclusion provides new insights into the role of alpha-synuclein in disease and into the factors that regulate the balance between solubility and aggregation of a natively unfolded protein.     

Thyroid C-cell hyperplasia in an adolescent with neurofibromatosis type 1

BACKGROUND: Subjects with neurofibromatosis type 1 (NF1) show an increased risk of endocrine tumors, especially pheochromocytoma, whereas thyroid C-cell hyperplasia (CCH) and medullary thyroid carcinoma (MTC) are very rare events described only in adult patients. METHOD: A case of CCH diagnosed in a 14-year-old girl affected with NF1 is reported. Calcitonin serum level after pentagastin was elevated (286 pg/ml). Genetic testing was performed in order to rule out mutations in the RET proto-oncogene. RESULT: No germline mutation previously reported in MEN2 was detected. Multifocal and bilateral CCH was demonstrated by immunohistochemistry. CONCLUSION: It is suggested that in such a genetic background of high risk for malignancy, CCH could be considered as an extremely rare condition likely preceding MTC.