Faculty Bibliography

Understanding the neural mechanisms underlying learning and memory in the entorhinal-hippocampal circuit is a central challenge of systems neuroscience. For more than 40 years, electrophysiological recordings in awake, behaving animals have been used to relate the receptive fields of neurons in this circuit to learning and memory. However, the vast majority of such studies are purely observational, as electrical, surgical, and pharmacological circuit manipulations are both challenging and relatively coarse, being unable to distinguish between specific classes of neurons. Recent advances in molecular genetic tools can overcome many of these limitations, enabling unprecedented control over neural activity in behaving animals. Expression of pharmaco- or optogenetic transgenes in cell-type-specific "driver" lines provides unparalleled anatomical and cell-type specificity, especially when delivered by viral complementation. Pharmacogenetic transgenes are specially designed neurotransmitter receptors exclusively activated by otherwise inactive synthetic ligands and have kinetics similar to traditional pharmacology. Optogenetic transgenes use light to control the membrane potential, and thereby operate at the millisecond timescale. Thus, activation of pharmacogenetic transgenes in specific neuronal cell types while recording from other parts of the circuit allows investigation of the role of those neurons in the steady state, whereas optogenetic transgenes allow one to determine the immediate network response.

Three strains capable of rapidly degrading TBBPA by co-metabolism and utilizing formate as the carbon source, named as J-F-01, J-F-02, and J-F-03, respectively, were isolated from enrichment cultures, which have been treated with 0.5mg/L TBBPA for 240 d. Based on morphology and 16S rRNA gene sequence analysis, both J-F-01 and J-F-02 were determined to Pseudomonas sp., while J-F-03 was identified as Streptococcus sp. A shorter half-life (6.1d) of TBBPA was observed in pure culture of J-F-03 when compared with J-F-01 (22.5d) and J-F-02 (13.6d). Surprisingly, the degradation of TBBPA was significantly enhanced by the mixed culture of J-F-02 and J-F-03. The optimal degradation conditions for the mixed cultures were determined. Under the optimal conditions, TBBPA (0.5mg/L) was completely metabolized by the mixed culture within ten days. Moreover, bromide and the metabolisms were detected, and a possible metabolic pathway was deduced from the detection of metabolite production patterns.

Solid lipid nanoparticles (SLNs) have emerged as an excellent substitute over polymeric nanoparticles and, when incorporated with chitosan which activates the macrophage to impart an immune response, produce excellent results to fight against deleterious diseases like leishmaniasis where its parasite diminishes the immunity of the host to induce resistance. Based upon this hypothesis, chitosan-coated SLNs were developed and loaded with amphotericin B (AmB) for immunoadjuvant chemotherapy of Leishmania infection. Both uncoated and chitosan-coated AmB-loaded SLNs (AmB-SLNs) were fabricated using solvent emulsification and evaporation method. The various processes and formulation parameters involved in AmB-SLN preparation were optimized with respect to particle size and stability of the particles. In vitro hemolytic test credited the formulations to be safe when injected in the veins. The cellular uptake analysis demonstrated that the chitosan-coated AmB-SLN was more efficiently internalized into the J774A.1 cells. The in vitro antileishmanial activity revealed their high potency against Leishmania-infected cells in which chitosan-coated AmB-SLNs were distinguishedly efficacious over commercial formulations (AmBisome and Fungizone). An in vitro cytokine estimation study revealed that chitosan-coated AmB-SLNs activated the macrophages to impart a specific immune response through enhanced production of TNF-alpha and IL-12 with respect to normal control. Furthermore, cytotoxic studies in macrophages and acute toxicity studies in mice evidenced the better safety profile of developed formulation in comparison to marketed formulations. This study indicates that the AmB-SLNs are a safe and efficacious drug delivery system which promises strong competence in antileishmanial chemotherapy and immunotherapy.

With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

Disorders in skin wound healing are a major health problem that requires the development of innovative treatments. The use of biomaterials as an alternative of skin replacement has become relevant, but its use is still limited due to poor vascularization inside the scaffolds, resulting in insufficient oxygen and growth factors at the wound site. In this study, we have developed a cell-based wound therapy consisting of the application of collagen-based dermal scaffolds containing mesenchymal stem cells from Wharton's jelly (WJ-MSC) in an immunocompetent mouse model of angiogenesis. From our comparative study on the secretion profile between WJ-MSC and adipose tissue-derived MSC, we found a stronger expression of several well-characterized growth factors, such as VEGF-A, angiopoietin-1 and aFGF, which are directly linked to angiogenesis, in the culture supernatant of WJ-MSC, both on monolayer and 3D culture conditions. WJ-MSC proved to be angiogenic both in vitro and in vivo, through tubule formation and CAM assays, respectively. Moreover, WJ-MSC consistently improved the healing response in vivo in a mouse model of human-like dermal repair, by triggering angiogenesis and further providing a suitable matrix for wound repair, without altering the inflammatory response in the animals. Since these cells can be easily isolated, cultured with high expansion rates and cryopreserved, they represent an attractive stem cell source for their use in allogeneic cell transplant and tissue engineering.