Citigroup Strategic Audit

An overview and analysis of the strategies, management, and financials of Citigroup. As well, this project concludes with a recommendation to restructure Citigroup\u27s current holdings to take advantage of their position in the global market. The analysis also recommends cost-cutting measures and management due to their current strategy and financial information

Preserving Dignity in the Long Term Care of Actively Dying Residents

As one goes through the process of aging and approaches death, they experience a series of losses: from the loss of physical or mental ability to the ultimate loss of life. These losses make the individual vulnerable to harms that can come from a variety of sources. One source is found within the everyday interactions of long-term care nurses and aides with their elderly, dying residents. Creating this harm stems from a poor nursing practice where the nurse or aide fails to recognize and promote the resident’s dignity and autonomy. The normal notion of dignity and autonomy does not encompass the humanity of residents. To assist the nurse in recognizing patient autonomy and dignity in the end of life, I expand the notion of dignity and autonomy while turning towards care ethics to create a just long-term care nursing practice. These four aims of long-term nursing care are: addressing the resident’s bodily and security needs, promoting the dignity of identity and recognizing the resident’s shifting sense of autonomy. In order to fulfill these aims, I point out several factors which increases the nurse or aide’s sense of work related stress and detracts from their ability to properly care for their residents. The management of the facility is ethically bound to address these points of stress in order to ensure the proper care of their staff and residents. One small solution I propose involves a three-step process to implement self-care in the workplace. I hypothesize that this solution will help to promote a less stressful, supportive nursing culture while decreasing medical interventions or the number of falls within the facility

Memory deficits in APP23/Abca1+/− mice correlate with the level of Aβ oligomers

ABCA1, a member of the ATP-binding cassette family of transporters, lipidates ApoE (apolipoprotein A) and is essential for the generation of HDL (high-density lipoprotein)-like particles in the CNS (central nervous system). Lack of Abca1 increases amyloid deposition in several AD (Alzheimer's disease) mouse models. We hypothesized that deletion of only one copy of Abca1 in APP23 (where APP is amyloid precursor protein) AD model mice will aggravate memory deficits in these mice. Using the Morris Water Maze, we demonstrate that 2-year-old Abca1 heterozygous APP23 mice (referred to as APP23/het) have impaired learning during acquisition, and impaired memory retention during the probe trial when compared with age-matched wild-type mice (referred to as APP23/wt). As in our previous studies, the levels of ApoE in APP23/het mice were decreased, but the differences in the levels of Aβ and thioflavin-S-positive plaques between both groups were insignificant. Importantly, dot blot analysis demonstrated that APP23/het mice have a significantly higher level of soluble A11-positive Aβ (amyloid β protein) oligomers compared with APP23/wt which correlated negatively with cognitive performance. To confirm this finding, we performed immunohistochemistry with the A11 antibody, which revealed a significant increase of A11-positive oligomer structures in the CA1 region of hippocampi of APP23/het. This characteristic region-specific pattern of A11 staining was age-dependent and was missing in younger APP23 mice lacking Abca1. In contrast, the levels of Aβ*56, as well as other low-molecular-mass Aβ oligomers, were unchanged among the groups. Overall, the results of the present study demonstrate that in aged APP23 mice memory deficits depend on Abca1 and are likely to be mediated by the amount of Aβ oligomers deposited in the hippocampus

Opposing effects ofApoe/Apoa1double deletion on amyloid-β pathology and cognitive performance in APP mice

Producción CientíficaATP binding cassette transporter A1 (encoded by ABCA1) regulates cholesterol efflux from cells to apolipoproteins A-I and E (ApoA-I and APOE; encoded by APOA1 and APOE, respectively) and the generation of high density lipoproteins. In Abca1 knockout mice (Abca1(ko)), high density lipoproteins and ApoA-I are virtually lacking, and total APOE and APOE-containing lipoproteins in brain substantially decreased. As the ε4 allele of APOE is the major genetic risk factor for late-onset Alzheimer's disease, ABCA1 role as a modifier of APOE lipidation is of significance for this disease. Reportedly, Abca1 deficiency in mice expressing human APP accelerates amyloid deposition and behaviour deficits. We used APP/PS1dE9 mice crossed to Apoe and Apoa1 knockout mice to generate Apoe/Apoa1 double-knockout mice. We hypothesized that Apoe/Apoa1 double-knockout mice would mimic the phenotype of APP/Abca1(ko) mice in regards to amyloid plaques and cognitive deficits. Amyloid pathology, peripheral lipoprotein metabolism, cognitive deficits and dendritic morphology of Apoe/Apoa1 double-knockout mice were compared to APP/Abca1(ko), APP/PS1dE9, and single Apoa1 and Apoe knockouts. Contrary to our prediction, the results demonstrate that double deletion of Apoe and Apoa1 ameliorated the amyloid pathology, including amyloid plaques and soluble amyloid. In double knockout mice we show that (125)I-amyloid-β microinjected into the central nervous system cleared at a rate twice faster compared to Abca1 knockout mice. We tested the effect of Apoe, Apoa1 or Abca1 deficiency on spreading of exogenous amyloid-β seeds injected into the brain of young pre-depositing APP mice. The results show that lack of Abca1 augments dissemination of exogenous amyloid significantly more than the lack of Apoe. In the periphery, Apoe/Apoa1 double-knockout mice exhibited substantial atherosclerosis and very high levels of low density lipoproteins compared to APP/PS1dE9 and APP/Abca1(ko). Plasma level of amyloid-β42 measured at several time points for each mouse was significantly higher in Apoe/Apoa1 double-knockout then in APP/Abca1(ko) mice. This result demonstrates that mice with the lowest level of plasma lipoproteins, APP/Abca1(ko), have the lowest level of peripheral amyloid-β. Unexpectedly, and independent of amyloid pathology, the deletion of both apolipoproteins worsened behaviour deficits of double knockout mice and their performance was undistinguishable from those of Abca1 knockout mice. Finally we observed that the dendritic complexity in the CA1 region of hippocampus but not in CA2 is significantly impaired by Apoe/Apoa1 double deletion as well as by lack of ABCA1. In conclusion: (i) plasma lipoproteins may affect amyloid-β clearance from the brain by the 'peripheral sink' mechanism; and (ii) deficiency of brain APOE-containing lipoproteins is of significance for dendritic complexity and cognition

Delivery of Antibody Mimics into Mammalian Cells via Anthrax Toxin Protective Antigen

Antibody mimics have significant scientific and therapeutic utility for the disruption of protein–protein interactions inside cells; however, their delivery to the cell cytosol remains a major challenge. Here we show that protective antigen (PA), a component of anthrax toxin, efficiently transports commonly used antibody mimics to the cytosol of mammalian cells when conjugated to the N-terminal domain of LF (LFN). In contrast, a cell-penetrating peptide (CPP) was not able to deliver any of these antibody mimics into the cell cytosol. The refolding and binding of a transported tandem monobody to Bcr-Abl (its protein target) in chronic myeloid leukemia cells were confirmed by co-immunoprecipitation. We also observed inhibition of Bcr-Abl kinase activity and induction of apoptosis caused by the monobody. In a separate case, we show disruption of key interactions in the MAPK signaling pathway after PA-mediated delivery of an affibody binder that targets hRaf-1. We show for the first time that PA can deliver bioactive antibody mimics to disrupt intracellular protein–protein interactions. This technology adds a useful tool to expand the applications of these modern agents to the intracellular milieu.Massachusetts Institute of Technology (Startup funds)Massachusetts Institute of Technology (MIT Reed Fund)National Science Foundation (U.S.) (NSF CAREER Award (CHE-1351807))Damon Runyon Cancer Research Foundation (award)National Science Foundation (U.S.) (Graduate Research Fellowship

A high-throughput synthetic platform enables the discovery of proteomimetic cell penetrating peptides and bioportides

Collectively, cell penetrating peptide (CPP) vectors and intrinsically active bioportides possess tremendous potential for drug delivery applications and the discrete modulation of intracellular targets including the sites of protein–protein interactions (PPIs). Such sequences are usually relatively short (< 25 AA), polycationic in nature and able to access the various intracellular compartments of eukaryotic cells without detrimental influences upon cellular biology. The high-throughput platform for bioportide discovery described herein exploits the discovery that many human proteins are an abundant source of potential CPP sequences which are reliably predicted using QSAR algorithms or other methods. Subsequently, microwave-enhanced solid phase peptides synthesis provides a high-throughput source of novel proteomimetic CPPs for screening purposes. By focussing upon cationic helical domains, often located within the molecular interfaces that facilitate PPIs, bioportides which act by a dominant-negative mechanism at such sites can be reliably identified within small number libraries of CPPs. Protocols that employ fluorescent peptides, routinely prepared by N-terminal acylation with carboxytetramethylrhodamine, further enable both the quantification of cellular uptake kinetics and the identification of specific site(s) of intracellular accretion. Chemical modifications of linear peptides, including strategies to promote and stabilise helicity, are compatible with the synthesis of second-generation bioportides with improved drug-like properties to further exploit the inherent selectivity of biologics

Estimation of hydraulic conductivity and its uncertainty from grain-size data using GLUE and artificial neural networks

peer reviewedaudience: researcher, professionalVarious approaches exist to relate saturated hydraulic conductivity (Ks) to grain-size data. Most methods use a single grain-size parameter and hence omit the information encompassed by the entire grain-size distribution. This study compares two data-driven modelling methods, i.e.multiple linear regression and artificial neural networks, that use the entire grain-size distribution data as input for Ks prediction. Besides the predictive capacity of the methods, the uncertainty associated with the model predictions is also evaluated, since such information is important for stochastic groundwater flow and contaminant transport modelling. Artificial neural networks (ANNs) are combined with a generalized likelihood uncertainty estimation (GLUE) approach to predict Ks from grain-size data. The resulting GLUE-ANN hydraulic conductivity predictions and associated uncertainty estimates are compared with those obtained from the multiple linear regression models by a leave-one-out cross-validation. The GLUE-ANN ensemble prediction proved to be slightly better than multiple linear regression. The prediction uncertainty, however, was reduced by half an order of magnitude on average, and decreased at most by an order of magnitude. This demonstrates that the proposed method outperforms classical data-driven modelling techniques. Moreover, a comparison with methods from literature demonstrates the importance of site specific calibration. The dataset used for this purpose originates mainly from unconsolidated sandy sediments of the Neogene aquifer, northern Belgium. The proposed predictive models are developed for 173 grain-size -Ks pairs. Finally, an application with the optimized models is presented for a borehole lacking Ks data