Evaluation of Novel B1R/B2R Agonists Containing TRIOZAN™ Nanoparticles for Targeted Brain Delivery of Antibodies in a Mouse Model of Alzheimer Disease.

The blood-brain barrier (BBB) is a major obstacle to the development of effective therapeutics for central nervous system (CNS) disorders, including Alzheimer's disease (AD). This has been particularly true in the case of monoclonal antibody (mAbs) therapeutic candidates, due to their large size. To tackle this issue, we developed new nanoformulations, comprising bio-based Triozan polymers along with kinin B1 and B2 receptor (B1R and B2R) peptide agonist analogues, as potent BBB-permeabilizers to enhance brain delivery of a new anti-C1q mAb for AD (ANX005). The prepared B1R/B2R-TRIOZAN™ nanoparticles (NPs) displayed aqueous solubility, B1R/B2R binding capacity and uniform sizes (~130-165 nm). The relative biodistribution profiles of the mAb loaded into these NPs versus the naked mAb were assessed in vivo through two routes of administrations (intravenous (IV), intranasal (IN)) in the Tg-SwDI mouse model of AD. At 24 h post-administration, brain levels of the encapsulated mAb were significantly increased (up to 12-fold (IV) and 5-fold (IN), respectively) compared with free mAb in AD brain affected regions, entorhinal cortex and hippocampus of aged mice. Liver uptakes remained relatively low with similar values for the nanoformulations and free mAb. Our findings demonstrate the potential of B1R/B2R-TRIOZAN™ NPs for the targeted delivery of new CNS drugs, which could maximize their therapeutic effectiveness.

Potentiation of B2 receptor signaling by AltB2R, a newly identified alternative protein encoded in the human bradykinin B2 receptor gene.

Recent functional and proteomic studies in eukaryotes (www.openprot.org) predict the translation of alternative open reading frames (AltORFs) in mature G-protein-coupled receptor (GPCR) mRNAs, including that of bradykinin B2 receptor (B2R). Our main objective was to determine the implication of a newly discovered AltORF resulting protein, termed AltB2R, in the known signaling properties of B2R using complementary methodological approaches. When ectopically expressed in HeLa cells, AltB2R presented predominant punctate cytoplasmic/perinuclear distribution and apparent cointeraction with B2R at plasma and endosomal/vesicular membranes. The presence of AltB2R increases intracellular [Ca2+] and ERK1/2-MAPK activation (via phosphorylation) following B2R stimulation. Moreover, HEK293A cells expressing mutant B2R lacking concomitant expression of AltB2R displayed significantly decreased maximal responses in agonist-stimulated Gαq-Gαi2/3-protein coupling, IP3 generation, and ERK1/2-MAPK activation as compared with wild-type controls. Conversely, there was no difference in cell-surface density as well as ligand-binding properties of B2R and in efficiencies of cognate agonists at promoting B2R internalization and ß-arrestin 2 recruitment. Importantly, both AltB2R and B2R proteins were overexpressed in prostate and breast cancers, compared with their normal counterparts suggesting new associative roles of AltB2R in these diseases. Our study shows that BDKRB2 is a dual-coding gene and identifies AltB2R as a novel positive modulator of some B2R signaling pathways. More broadly, it also supports a new, unexpected alternative proteome for GPCRs, which opens new frontiers in fields of GPCR biology, diseases, and drug discovery.

Functionalization of Mesoporous Carbon Materials for Selective Separation of Lanthanides under Acidic Conditions.

New functional mesoporous carbon sorbents were successfully synthesized to overcome some issues of solid-liquid extraction (e.g., selectivity, extraction capacity, and reusability under acidic conditions) in production of pure lanthanides (Ln). Wet-oxidation technique was performed to increase the surface reactivity of pristine ordered mesoporous carbon (OMC), and, in a second step, a surface modification using diglycolamide-based (DGA-based) selective ligands toward Ln was performed. Two types of ligands were tested: the first contains a long spacer (e.g., between carbon support and chelating function), and the second has a shorter one. These materials have been characterized by X-ray photoelectron spectroscopy (XPS), low-angle X-ray diffraction (XRD), thermogravimetric analysis, nitrogen sorption, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). These analyses confirmed that the carbon mesostructure was maintained after organo-functionalization of the surface and showed the covalent attachment of selective ligands. These new materials, and especially the system with a short spacer between the ligand and the surface, reveal unique Ln selectivity profiles with improved extraction performances for the recovery of lanthanides, in terms of both selectivity and adsorption capacity, and unprecedented stability under acidic conditions.

Modification of the Assessment of Life Habits (LIFE-Hm) to consider personalized satisfaction with participation in activities and roles: results from a construct validity study with older adults.

PURPOSE: Participation, defined as a person's involvement in activities and roles, is a primary intervention goal in rehabilitation. To achieve client-centered practice, rehabilitation professionals need to go beyond objective accomplishment criteria and consider satisfaction with and the importance of participation in activities and roles. To our knowledge, no instrument considers accomplishment, satisfaction and importance of activities and roles, and allows numerical scoring and comparison. The objectives of this study were to modify the Assessment of Life Habits questionnaire (LIFE-Hm) to consider personalized satisfaction (satisfaction weighted by importance) with participation in activities and roles, and to: (1) examine its convergent validity with quality of life (QOL) and (2) compare the associations between QOL on the one hand and, satisfaction (LIFE-H) and personalized satisfaction (LIFE-Hm) with participation on the other. METHOD: A descriptive cross-sectional study was conducted with 84 older adults, average age 76 years, with different functional autonomy levels. RESULTS: Quality of life was associated with personalized satisfaction for all categories of activities and roles (r = 0.45 to 0.75; p < 0.001). These associations differed significantly from the associations with satisfaction for the "housing", "mobility" and "responsibilities" categories (p = 0.04 to 0.0047). CONCLUSIONS: This study found good construct validity of the LIFE-Hm with QOL. Personalization can add value in achieving client-centered practice. Implications for Rehabilitation The LIFE-Hm becomes the first instrument available in English and French that allows comparison between individuals and informs rehabilitation professionals about the level of accomplishment, satisfaction and personalized satisfaction with participation in activities and roles. Personalized satisfaction can add value in achieving client-centered practice as it considers not only how satisfying activities and roles are for the person, but also the importance that these activities and roles have for her/him. The LIFE-Hm offers the advantage of systematically identifying activities and roles which are not satisfactory but are important for the client and have the potential to be improved (lower accomplishment level).

Development and validation of an instrument measuring individual empowerment in relation to personal health care: the Health Care Empowerment Questionnaire (HCEQ).

PURPOSE: The purpose of this study was to develop and validate a questionnaire that measures the degree of individual empowerment in relation to personal health care and services. DESIGN: The questionnaire was developed by identifying individual empowerment indicators from the literature, generating corresponding items, and pretesting the tool with older persons. SETTING: The Health Care Empowerment Questionnaire (HCEQ) was developed and validated with subjects participating in the Program of Research to Integrate Services for the Maintenance of Autonomy (PRISMA) in the Sherbrooke and Quebec City area. SUBJECTS: Eight hundred seventy-three subjects agreed to participate, for a response rate of 56.28%. The mean ages of men and women were 81.1 and 82.4 years, respectively. Analysis. Factor analysis (exploratory and confirmatory) determined the validity of the questionnaire, and the reliability was assessed using measures of internal consistency and temporal stability (test-retest). RESULTS: The multidimensional nature of the concept of individual empowerment was confirmed by three factors that explain more than 68% of the total variance. The Cronhbach's alpha coefficient of internal consistency was .83 and the intraclass correlation coefficients (test-retest) was .70 (95% CI: .48-.83). CONCLUSION: In light of these findings, the characteristics and multidimensional perspective of the HCEQ appear to be useful in advancing knowledge about individual empowerment in relation to personal health care and services.

Development and validation of the Health Care Satisfaction Questionnaire (HCSQ) in elders.

The Health Care Satisfaction Questionnaire (HCSQ) was designed for the evaluation of health care and services in a manner that controls acquiescence bias yet is characterized by a simple structure. The HCSQ was developed and validated within the context of the Program of Research to Integrate Services for the Maintenance of Autonomy (PRISMA) in the Sherbrooke and Quebec City areas of Quebec, Canada. Exploratory and confirmatory factor analyses were done with 873 subjects and confirmed the multidimensional nature of the concept of satisfaction. Three factors explained more than 52% of the total variance. The analysis of internal consistency produced Cronbach alpha coefficients of .93, .74, and .78 for Factors 1, 2, and 3, respectively. The alpha of the overall scale was .92. The intraclass correlation coefficient (test-retest) for the entire scale was .72 (95% CI: .52-.84). In light of these findings, the characteristics and multidimensional perspective of the HCSQ appear to be useful for measuring and advancing knowledge about health care and services satisfaction.