Design of a novel class of biphenyl CETP inhibitors

A new class of CETP inhibitors was designed and prepared. These compounds are potent both in vitro and in vivo. The most active compound (12d) has shown an ability to raise HDL significantly in transgenic mouse PD model.     

Agonistic encounters and cellular angst: social interactions induce heat shock proteins in juvenile salmonid fish

Juvenile salmonid fish readily form dominance hierarchies when faced with limited resources. While these social interactions may result in profound behavioural and physiological stress, it is unknown if this social stress is evident at the level of the cellular stress response—specifically, the induction of stress or heat shock proteins (Hsps). Thus, the goal of our study was to determine if Hsps are induced during hierarchy formation in juvenile rainbow trout (Oncorhynchus mykiss). To this end, we measured levels of three Hsps, Hsp70, Hsc (heat shock cognate)70 and Hsp90 in the white muscle, liver and brain of trout that had been interacting for 36 h, 72 h or 6 days. Our data indicate that Hsps are induced in both dominant and subordinate fish in a time- and tissue-specific manner. In further mechanistic experiments on fasted and cortisol-treated fish, we demonstrated that high plasma cortisol does not affect Hsp induction in trout white muscle or liver, but both conditions may be part of the mechanism for Hsp induction with social stress in the brain. We conclude that the behavioural and physiological stress experienced by juvenile rainbow trout in dominance hierarchies can be extended to the induction of Hsps.     

Intracellular delivery of a protein antigen with an endosomal-releasing polymer enhances CD8 T-cell production and prophylactic vaccine efficacy

Protein-based vaccines have significant potential as infectious disease and anticancer therapeutics, but clinical impact has been limited in some applications by their inability to generate a coordinated cellular immune response. Here, a pH-responsive carrier incorporating poly(propylacrylic acid) (PPAA) was evaluated to test whether improved cytosolic delivery of a protein antigen could enhance CD8+ cytotoxic lymphocyte generation and prophylactic tumor vaccine responses. PPAA was directly conjugated to the model ovalbumin antigen via reducible disulfide linkages and was also tested in a particulate formulation after condensation with cationic poly(dimethylaminoethyl methacrylate) (PDMAEMA). Intracellular trafficking studies revealed that both PPAA-containing formulations were stably internalized and evaded exocytotic pathways, leading to increased intracellular accumulation and potential access to the cytosolic MHC-1 antigen presentation pathway. In an EG.7-OVA mouse tumor protection model, both PPAA-containing carriers robustly inhibited tumor growth and led to an approximately 3.5-fold increase in the longevity of tumor-free survival relative to controls. Mechanistically, this response was attributed to the 8-fold increase in production of ovalbumin-specific CD8+ T-lymphocytes and an 11-fold increase in production of antiovalbumin IgG. Significantly, this is one of the first demonstrated examples of in vivo immunotherapeutic efficacy using soluble protein-polymer conjugates. These results suggest that carriers enhancing cytosolic delivery of protein antigens could lead to more robust CD8+ T-cell response and demonstrate the potential of pH-responsive PPAA-based carriers for therapeutic vaccine applications.     

High prevalence but relatively low impact of two eucharitid parasitoids attacking the Neotropical ant Ectatomma tuberculatum (Olivier)

Composition and dynamics of ant communities may be influenced by highly specialized, specific parasitoids such as eucharitids. Yet, little is known about their prevalence in ant societies. Through systematic monthly excavation of ant nests, we evaluated the impact on the Neotropical ant Ectatomma tuberculatum of two eucharitid parasitoid species, Dilocantha lachaudii and Isomerala coronata, which simultaneously attack the same host populations in southern Mexico. Nearly 90% of all the nests collected through the year were parasitized, with an average of 13% ant pupae and 6.7% ant larvae parasitized by eucharitids, and an annual loss of 17% of the ant brood. Eucharitid prevalence among host nests was, however, very variable, and only some E. tuberculatum nests were severely weakened (100% of ant brood parasitized). Parasitism was highest during the dry season (January–March), just when the production of ant pupae was minimum: up to 50.6% of the ant pupae were destroyed in March. However, production of E. tuberculatum males and females occurred later (June–July), and the reproductive potential of the host colonies did not ultimately seem to be heavily affected by eucharitid parasitism. Differences in the seasonal timing of eucharitid attack and ant reproduction thus have the potential to modulate the impact of eucharitids on ants. Our results are discussed in the context of the impact of eucharitids upon E. tuberculatum colonies and their possible effect on the community structure of this potential biocontrol agent ant.     

Cryopreservation of human bone marrow‐derived mesenchymal stem cells with reduced dimethylsulfoxide and well‐defined freezing solutions

The aim of this study is to investigate the feasibility of using well defined, serum‐free freezing solutions with a reduced level of dimethylsulfoxide (DMSO) of 7.5, 5, and 2.5% (v/v) in the combination with polyethylene glycol (PEG) or trehalose to cryopreserve human bone marrow‐derived mesenchymal stem cells (hBMSCs), a main source of stem cells for cell therapy and tissue engineering. The standard laboratory freezing protocol of around 1°C/min was used in the experiments. The efficiency of 1,2‐propandiol on cryopreservation of hBMSCs was explored. We measured the post‐thawing cell viability and early apoptotic behaviors, cell metabolic activities, and growth dynamics. Cell morphology and osteogenic, adipogenic and chondrogenic differentiation capability were also tested after cryopreservation. The results showed that post‐thawing viability of hBMSCs in 7.5% DMSO (v/v), 2.5% PEG (w/v), and 2% bovine serum albumin (BSA) (w/v) was comparable with that obtained in conventional 10% DMSO, that is, 82.9 ± 4.3% and 82.7 ± 3.7%, respectively. In addition, 5% DMSO (v/v) with 5% PEG (w/v) and 7.5% 1,2‐propandiol (v/v) with 2.5% PEG (w/v) can provide good protection to hBMSCs when 2% albumin (w/v) is present. Enhanced cell viability was observed with the addition of albumin to all tested freezing solutions. © 2010 American Institute of Chemical Engineers Biotechnol. Prog., 2010     

Initial development and structure of biofilms on microbial fuel cell anodes

Background  

Microbial fuel cells (MFCs) rely on electrochemically active bacteria to capture the chemical energy contained in organics and convert it to electrical energy. Bacteria develop biofilms on the MFC electrodes, allowing considerable conversion capacity and opportunities for extracellular electron transfer (EET). The present knowledge on EET is centred around two Gram-negative models, i.e. Shewanella and Geobacter species, as it is believed that Gram-positives cannot perform EET by themselves as the Gram-negatives can. To understand how bacteria form biofilms within MFCs and how their development, structure and viability affects electron transfer, we performed pure and co-culture experiments.     

Optimal control of a rabies epidemic model with a birth pulse

A system of ordinary differential equations describes the population dynamics of a rabies epidemic in raccoons. The model accounts for the dynamics of a vaccine, including loss of vaccine due to animal consumption and loss from factors other than racoon uptake. A control method to reduce the spread of disease is introduced through temporal distribution of vaccine packets. This work incorporates the effect of the seasonal birth pulse in the racoon population and the attendant increase in new-borns which are susceptible to the diseases, analysing the impact of the timing and length of this pulse on the optimal distribution of vaccine packets. The optimization criterion is to minimize the number of infected raccoons while minimizing the cost of distributing the vaccine. Using an optimal control setting, numerical results illustrate strategies for distributing the vaccine depending on the timing of the infection outbreak with respect to the birth pulse.