919 resultados para Responsive


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The t(15;17) chromosomal translocation, specific for acute promyelocytic leukemia (APL), fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene, resulting in expression of a PML-RAR alpha hybrid protein. In this report, we analyzed the nature of PML-RAR alpha-containing complexes in nuclear protein extracts of t(15;17)-positive cells. We show that endogenous PML-RAR alpha can bind to DNA as a homodimer, in contrast to RAR alpha that requires the retinoid X receptor (RXR) dimerization partner. In addition, these cells contain oligomeric complexes of PML-RAR alpha and endogenous RXR. Treatment with retinoic acid results in a decrease of PML-RAR alpha protein levels and, as a consequence, of DNA binding by the different complexes. Using responsive elements from various hormone signaling pathways, we show that PML-RAR alpha homodimers have altered DNA-binding characteristics when compared to RAR alpha-RXR alpha heterodimers. In transfected Drosophila SL-3 cells that are devoid of endogenous retinoid receptors PML-RAR alpha inhibits transactivation by RAR alpha-RXR alpha heterodimers in a dominant fashion. In addition, we show that both normal retinoid receptors and the PML-RAR alpha hybrid bind and activate the peroxisome proliferator-activated receptor responsive element from the Acyl-CoA oxidase gene, indicating that retinoids and peroxisome proliferator receptors may share common target genes. These properties of PML-RAR alpha may contribute to the transformed phenotype of APL cells.

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Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

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Salt taste in mammals can trigger two divergent behavioural responses. In general, concentrated saline solutions elicit robust behavioural aversion, whereas low concentrations of NaCl are typically attractive, particularly after sodium depletion. Notably, the attractive salt pathway is selectively responsive to sodium and inhibited by amiloride, whereas the aversive one functions as a non-selective detector for a wide range of salts. Because amiloride is a potent inhibitor of the epithelial sodium channel (ENaC), ENaC has been proposed to function as a component of the salt-taste-receptor system. Previously, we showed that four of the five basic taste qualities-sweet, sour, bitter and umami-are mediated by separate taste-receptor cells (TRCs) each tuned to a single taste modality, and wired to elicit stereotypical behavioural responses. Here we show that sodium sensing is also mediated by a dedicated population of TRCs. These taste cells express the epithelial sodium channel ENaC, and mediate behavioural attraction to NaCl. We genetically engineered mice lacking ENaCalpha in TRCs, and produced animals exhibiting a complete loss of salt attraction and sodium taste responses. Together, these studies substantiate independent cellular substrates for all five basic taste qualities, and validate the essential role of ENaC for sodium taste in mice.

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PPARs (peroxisome-proliferator-activated receptors) alpha, beta/delta and gamma are a group of transcription factors that are involved in numerous processes, including lipid metabolism and adipogenesis. By comparing liver mRNAs of wild-type and PPARalpha-null mice using microarrays, a novel putative target gene of PPARalpha, G0S2 (G0/G1 switch gene 2), was identified. Hepatic expression of G0S2 was up-regulated by fasting and by the PPARalpha agonist Wy14643 in a PPARalpha-dependent manner. Surprisingly, the G0S2 mRNA level was highest in brown and white adipose tissue and was greatly up-regulated during mouse 3T3-L1 and human SGBS (Simpson-Golabi-Behmel syndrome) adipogenesis. Transactivation, gel shift and chromatin immunoprecipitation assays indicated that G0S2 is a direct PPARgamma and probable PPARalpha target gene with a functional PPRE (PPAR-responsive element) in its promoter. Up-regulation of G0S2 mRNA seemed to be specific for adipogenesis, and was not observed during osteogenesis or myogenesis. In 3T3-L1 fibroblasts, expression of G0S2 was associated with growth arrest, which is required for 3T3-L1 adipogenesis. Together, these data indicate that G0S2 is a novel target gene of PPARs that may be involved in adipocyte differentiation.

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The NeO'liberal State and the Crisis ofPublic Service Broadcasting in the Anglo-American Democracies The purpose ofthis analysis ofthe present condition ofpublic service broadcasting in the Anglo- American democracies was to investigate whether such media can still be regarded as the primarypublic spherefor a dialogue between each nation 's civil society and the State. The motivationfor this thesis was based on a presumption that such fora for public discussion on the central issues of each society have become viewed as less relevant bypoliticians andpolicy-makers and thepublics they were intended to serve in the Anglo-American democracies over thepast two decades. It is speculated that this is the case because ofa beliefthat the post-war consensus between the respective States andpublics that led to the construction of the Keynesian Welfare State and the notion ofpublic service broadcasting has been displaced by an individualistic, neo-liberal, laissez-faire ideology. In other words, broadcasting as a consumer-oriented, commercial commodity has superseded concerns pertaining to the importance ofthe public interest. The methodology employed in this thesis is a comparative analysisfrom a criticalpolitical economy perspective. It was considered appropriate to focus on the United Kingdom, Australia, Canada and the\ United States because they comprise the four largest Anglo-American nations with democratic political systems andprimarily market economies. Justificationfor this particular sample is reinforced by thefact that case study countries also share a common socio-political and economic tradition. The evidence assembledfor this thesis consisted almost exclusively ofexisting literature on the subjects ofpublic service broadcasting, global economic andpolitical integration, and the ascendance ofthe 'free-market ' ethos in Western democracies since the late mid- to late-1970s. In essence, this thesis could be considered as a reinterpretation ofthe existing literature relevant to these issues. Several important common features werefound among the political, economic and broadcasting systems of the four case study nations. It is proposed that the prevalence of the neo-liberal world view throughout the political and policy environments of the four countries has undermined the stability and credibility of each nation 's national public service broadcasting organization, although with varying intensity and effect,. Deregulation ofeach nation 's broadcasting system and the supremacy ofthe notion of 'consumer sovereignty' have marginalized the view of broadcasting on any basis other than strictly economic criteria in thefour case study countries. This thesis concludes that,for a reconstruction ofa trulyparticipatory anddemocraticpublicsphere to be realized in the present as well as thefuture, a reassessment ofthe conventional concept ofthe 'public sphere ' is necessary. Therefore, it is recommended that thefocus ofpolicy-makers in each Anglo-American democracy be redirectedfrom that which conceived ofan all-encompassing, large, state-ownedand operated public broadcasting service toward a view which considers alternativeforms ofpublic communication, such as local community and ethnic broadcasting operations, that are likely to be more responsive to the needs of the increasingly diverse and heterogeneous populations that comprise the modem Anglo-American democracies. The traditional conception of public broadcasters must change in accordance with its contemporary environment if the fundamental principles of the public sphere and public service broadcasting are to be realized.

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Mammalian heterotherms, such as hibemators, are known to be more tolerant of low oxygen tensions than their homeothermic counterparts. It has been suggested that this relative hypoxia tolerance is related to their ability to deal with dramatic changes in body temperature during entry to and arousal from torpor. However, hibemators demonstrate dramatic seasonality in both daily heterothermy and overall torpor expression. It was of interest to test if seasonal comparisons of normothermic individuals within a single species with the capacity to hibernate produce changes in the response to hypoxia that would reflect a seasonal change in tolerance to low oxygen. In particular, the species studied, the Eastern chipmunk {Tamias striatus), is known to enter into torpor exclusively in the winter. To test for seasonal differences in the metabolic and thermoregulatory responses to hypoxia, flow-through respirometry was used to compare metabolic rate, minimum thermal conductance, body temperature, and a thermal gradient used to assess selected ambient temperature in response to hypoxia in both summer and winter acclimated animals. Although the animals periodically expressed torpor throughout the winter, no differences between season in resting metabolic rate, body temperature or minimum thermal conductance were observed in normoxia. The metabolic trials indicated that chipmunks are less responsive to hypoxia in the winter than they are in the summer. Although body temperature dropped in response to hypoxia in both seasons, the decrease was less in the winter, and there was no corresponding decrease in metabolic rate. Providing the animals with a choice of ambient temperatures in hypoxia resulted in a blunting of the drop in body temperature in both seasons, suggesting that the reported fall in body temperature set point in hypoxia is not fully manifested in the behavioural pathways responsible for thermoregulation in chipmunks. Instead, body temperature in hypoxia appears to be highly dependent on ambient temperature and oxygen concentration. The results of this study suggest that the season in which the responses to hypoxia are measured is important, especially in a heterotherm where seasonality can affect the degree to 1 which the animal is tolerant of hypoxia. Winter-acclimated chipmunks appear more capable of defending metabolic heat production in hypoxia, a response consistent with the increased thermogenic capacity observed in animals that must periodically enter and arouse from torpor during hibernation.

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This study examined the strategies used by elementary school principals to facilitate and nurture the development of professional learning communities (PLC) within their school settings. Using a reputational sample of administrators whose schools were demonstrating observable characteristics of PLCs, this study documented and described the strategies and actions taken by the principals to move their schools forward. Data collection included the use of open-ended interviews as well as observations capturing the means by which the principals addressed the areas of culture, processes, and structures within their school setting. A grounded theory approach to data analysis uncovered 4 guiding principles used by the principals to facilitate the development of the PLCs within their school: (a) protecting the purpose; (b) attending to relationships; (c) sharing the responsibility; and (d) valuing the journey. The guiding principles were used by each administrator to anchor the decisions they made and develop responsive, contextspecific strategies to support the PLC at their school. The results highlighted the complex role of the principal and the supports required to tackle the difficult work of facilitating PLCs.

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Efforts to reform the public sector reflect the social, political and economic environment within which government must function. The recent demands by the public for more consensual decision-making, as well as more efficient, effective and responsive public service, have resulted in a number of reform initiatives, including an emphasis on partnership development. The purpose of this thesis is to examine partnership arrangements within the public sector. Specifically, the thesis will assess the value of partnerships and their impact on government by examining six partnership arrangements involving the Ontario Ministry of Natural Resources (OMNR). The OMNR, having recently been awarded the 1992 Institute of Public Administration of Canada Award for Innovative Management, on the theme of partnership development, is being lauded as an example for other government agencies considering similar alliances. The thesis begins by introducing the concept and practice of partnership within the public sector in general and the OMNR specifically. Descriptive analysis of six OMNR partnerships is provided and a number of criteria are used to determine the success of each of these arrangements. Special attention is paid to the political implications of partnerships and to those attributes which appear to contribute to the successful establishment and iii maintenance of partnership arrangements. The conclusion is drawn that partnerships provide the government with an opportunity to address public demands for greater involvement in decision-making while accommodating government's limited financial resources. However, few truly collaborative partnerships exist within the public sector. There are also significant political implications associated with partnerships which must be dealt with both at the political and bureaucratic levels of government. Lastly, it is argued that while partnerships within the OMNR are experiencing some difficulties, they constitute a genuine attempt to broaden the base of decision-making and to incorporate the concerns of stakeholders into resource management.

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Chicl( brain growth factor (CBGF) is a mitogen isolated from embryonic chick brains thought to have a potential role as a trophic factor involved in nerve dependent amphibian limb regeneration. In addition, CBGF stimulates 3H-thymidine incorporation in chick embryo brain astrocytes in vitro. In this study, cultured chick embryo brain non-neuronal cells were employed in a bioassay to monitor CBGF activity throughout various stages of its pllrification. Cell culture and assay conditions were optimized. Nonneuronal cells grew best on collagen-coated culture dishes in complete medium, were most responsive to a growth stimulus [10% fetal bovine serum (FBS)] at the second and third subcultures, and were healthiest when rendered "quiescent" in medium supplemented with 1% FBS. The most effective bioassay conditions consisted of a minimum 14.5 hour "quiescence" time (24 hours was used), a 6 hour "prestimulation" time, and a 24 hour 3H-thymidine labeling time. Four-day subconfluent primary non-neuronal cells consisted of 6.63% GFAP positive cells; as a result cultures were thought to be mainly composed of astroblasts. CBGF was purified from 18-day chick embryo brains by ultrafiltration through Amicon PM-30 and YM-2 membranes, size exclusion chromatography through a Biogel P6 column, and analytical reverse-phase high-performance liquid chromatography (rp-HPLC). The greatest activity resided in rp-HPLC fraction #7 (10 ng/ml) which was as effective as 10% FBS at stimulating 3H-thymidine incorporation in chick embryo brain nonneuronal cells. Although other researchers report the isolation of a mitogenic fraction consisting of 5'-GMP from the embryonic chick brain, UV absorbance spectra, rp-HPLC elution profiles, and fast atom bombardment (FAB) mass spectra indicated that CBGF is neither 5'-GMP nor 51-AMP. 2 Moreover, commercially available 5t-GMP was inhibitory to 3H-thymidine incorporation in the chick non-neuronal cells, while Sf-AMP had no effect. Upon treatment with pronase, the biological activity of fraction P6-3 increased; this increase was nearly 30% greater than what would be expected from a simple additive effect of any mitogenic activity of pronase alone together with P6-3 alone. This may suggest the presence of an inhibitor protein. The bioactive component may be a protein protected by a nucleoside/nucleotide or simply a nucleoside/nucleotide acting alone. While the FAB mass spectrum of rp-HPLC fraction #7 did not reveal molecular weight or sequence information, the ion of highest molecular weight was observed at m/z 1610; this is consistent with previous estimations of CBGF's size. 3

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We examined the cognitive and emotional sequelae following mild head injury (MHI; e.g., concussion) in high-functioning individuals and whether persons with MHI pre~ent, both physiologically and via self-report, in a manner different from (i.e., underaroused) that of persons who have no history of head injury. We also investigated the effect arousal state ~as on the cognitive performance of this population. Using a quasiexperimental research design (N = 91), we examined changes in attention, working memory, and cognitive flexibility (subtests ofthe WAIS-III, 1997,WMS-III, 1997, & DKEFS, 2002) as a function of manipulated arousal (i.e., induced psychosocial stress/activation; reduced activation/relaxation). In addition to self-reported arousal and state anxiety (State-Trait Anxiety Inventory; Speilberger, 1983a) measures, physiological indices of arousal state (i.e., electrodermal responsivity, heart rate, and respiration activity) were recorded (via Polygraph Professional Suite, 2008) across a 2.5 hour interval while completing various cognitive tasks. Students also completed the Post-concussive Symptom Checklist (Gouvier et aI., 1992). The results demonstrate that university students who report a history ofMHI (i.e., "altered state of consciousness") experience significantly lower levels of anxiety, were physiologically underaroused, and were less responsive to stressors in their environment, compared to their non-~HI cohorts. As expected, cognitive flexibility (but not other neuropsychological measures of cognition) was advantaged with increased stress, and disadvantaged with reduced stress, in persons with reported MHI, but not for those without reported MHI which provided limited support for our hypothesis. Further, university students who had no complaints related to their previous MHI endorsed a greater number of traditional post-concussive symptoms in terms of intensity, duration and frequency as compared to students who did not report a MHI. The underarousal in traumatic brain injury has been associated with (ventromedial prefrontal cortex) VMPFC disruption and may be implicated in MHI generally. Students who report sustaining a previous MHI may be less able to physiologically respond and/or cognitively appraise, stressful experiences as compared to their no-MHI cohort and experience persistent, long-lasting consequences despite the subtle nature of a history of head injury.

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Vitamin E is a well known fat soluble chain breaking antioxidant. It is a general tenn used to describe a family of eight stereoisomers of tocopherols. Selective retention of a-tocopherol in the human circulation system is regulated by the a -Tocopherol Transfer Protein (a-TIP). Using a fluorescently labelled a-tocopherol (NBD-a-Toc) synthesized in our laboratory, a fluorescence resonance energy transfer (FRET) assay was developed to monitor the kinetics of ligand transfer by a-hTTP in lipid vesicles. Preliminary results implied that NBD-a-Toe simply diffused from 6-His-a-hTTP to acceptor membranes since the kinetics of transfer were not responsive to a variety of conditions tested. After a series of trouble shooting experiments, we identified a minor contaminant, E coli. outer membrane porin F (OmpF) that co-purified with 6-His-a-hTTP from the metal affinity column as the source of the problem. In order to completely avoid OmpF contamination, a GST -a-hTTP fusion protein was purified from a glutathione agarose column followed by an on-column thrombin digestion to remove the GST tag. We then demonstrated that a-hTTP utilizes a collisional mechanism to deliver its ligand. Furthennore, a higher rate of a-tocopherol transfer to small unilamellar vesicles (SUV s) versus large unilamellar vesicles (LUV s) indicated that transfer is sensitive to membrane curvature. These findings suggest that ahTTP mediated a-Toc transfer is dominated by the hydrophobic nature of a-hTTP and the packing density of phospholipid head groups within acceptor membranes. Based on the calculated free energy change (dG) when a protein is transferred from water to the lipid bilayer, a model was generated to predict the orientation of a-hTTP when it interacts with lipid membranes. Guided by this model, several hydrophobic residues expected to penetrate deeply into the bilayer hydrophobic core, were mutated to either aspartate or alanine. Utilizing dual polarization interferometry and size exclusion vesicle binding assays, we identified the key residues for membrane binding to be F 165, F 169 and 1202. In addition, the rates of ligand transfer of the u-TTP mutants were directly correlated to their membrane binding capabilities, indicating that membrane binding was likely the rate limiting step in u-TTP mediated transfer of u-Toc. The propensity of u-TTP for highly curved membrane provides a connection to its colocalization with u-Toc in late endosomes.

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The importance of father involvement in the young family is increasingly evident. This research was conducted using the theory of planned behaviour to understand important aspects contributing to father invo lvement in the breastfeeding process. Eighty mothers and 65 fathers of one-year-old children completed a questionnaire regarding father involvement (FI) in breastfeeding. Measures included attitudes, subjective norms, and perceived behaviour control regarding FI and the extent to which fathers demonstrated involvement by advocating for and affIrming breastfeeding, being present during breastfeeding, providing household help, and being responsive to their partners' needs. Results suggest that mothers and fathers experience FI differently. Mothers' perceptions are motivated by intrinsic attitudinal considerations, whereas fathers' involvement is primarily motivated by the opinions of others. Interventions should focus on increasing fathers' perception of societal approval through approaches such as peer-led groups, and increasing mothers' approval through information of the value of fathers' involvement in the breastfeeding process.

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Orosensory perception strongly influences liking and consumption of foods and beverages. This thesis examines the influence of biological sources of individual variation on the perception of prototypical orosensory stimuli, food liking, self-reported alcohol liking and consumption, and indices of health. Two orosensory indices were examined: propylthiouracil (PROP) responsiveness, a genetically-mediated index of individual variation associated with enhanced responsiveness to orosensory stimuli often expressed as PROP taster status (PTS); and thermal taster status (TTS), a recently reported index of orosensory responsiveness. Taster status in PTS and/or TTS confers greater responsiveness to most orosensory stimuli. Gender, age, ethnicity, and fungiform papillae (FP) density were not associated with orosensory responsiveness to tastants, an astringent, and a flavour. Unlike PROP responsiveness, FP density was not associated with TTS. Both PROP responsiveness and TTS were associated with increased responsiveness to orosensory stimuli, including temperature and astringency. For PROP, this association did not hold when stimuli were presented at cold or warm temperatures, which are ecologically valid since most foods and beverages are not consumed at ambient temperature. Thermal tasters (TTs), who perceive 'phantom' taste sensations with lingual thermal stimulation, were more responsive to stimuli at both temperatures than thermal non-tasters (TnTs). While PTS, TIS, and gender affected self-reported liking and consumption of some alcoholic beverages, gender associated with the greatest number of beverage types and consumption parameters, with males generally liking and consuming alcoholic beverages more than females. Age and gender were the best predictors of alcoholic beverageAiking and consumption. As expected, .. liking of bitter and fatty foods and cream was inversely related to PROP responsiveness. TTS did not associate with body mass index or waist circumference, and contrary to previous studies, neither did PROP responsiveness. Taken together, TnTs' greater liking of cooked fruits and vegetables and high alcohol, and astringent alcoholic beverages than TTs suggests differences between TTS groups may be driven by perceived temperature and texture. Neither an interaction between PTS and TTS nor a TTS effect on PROP responsiveness was observed, suggesting these two indices of individual variation exert their influences on orosensory perception independently.

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This thesis explores Aboriginal women's access to and success within universities through an examination of Aboriginal women's educational narratives, along with input from key service providers from both the Aboriginal and non-Aboriginal community. Implemented through the Wildfire Research Method, participants engaged in a consensusbased vision of accessible education that honours the spiritual, emotional, intellectual, and physical elements necessary for the success of Aboriginal women in university. This study positions Aboriginal women as agents of social change by allowing them to define their own needs and offer viable solutions to those needs. Further, it connects service providers from the many disconnected sectors that implicate Aboriginal women's education access. The realities of Aboriginal women are contextualized through historical, sociocultural, and political analyses, revealing the need for a decolonizing educational approach. This fosters a shift away from a deficit model toward a cultural and linguistic assets based approach that emphasizes the need for strong cultural identity formation. Participants revealed academic, cultural, and linguistic barriers and offered clear educational specifications for responsive and culturally relevant programming that will assist Aboriginal women in developing and maintaining strong cultural identities. Findings reveal the need for curriculum that focuses on decolonizing and reclaiming Aboriginal women's identities, and program outcomes that encourage balance between two worldviews-traditional and academic-through the application of cultural traditions to modern contexts, along with programming that responds to the immediate needs of Aboriginal women such as childcare, housing, and funding, and provide an opportunity for universities and educators to engage in responsive and culturally grounded educational approaches.

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This qualitative case study explored 10 young female Shi’i Muslim Arabic-Canadian students’ experiences associated with wearing the Hijab (headscarf) within their home, community, and predominantly White Canadian public elementary school environments. The study integrated several bodies of scholarly theories in order to examine the data under a set of comprehensive lenses that more fully articulates and theorizes on the diversity of female Shi’i Muslim Canadian students’ experiences. These theories are: identity theories with a focus on religious identity and negative stereotypes associated with Muslims; feminism and the Hijab discourses; research pertaining to Muslims in school settings; and critical race theory. In order to readdress the dearth of information about Shi’is’ experiences in schools, this study provides an in-depth case study analysis in which the methodology strategies included 10 semi-structured in-depth interviews, 2 focus-group meetings, and the incorporation of the researcher’s fieldnotes. Data analysis revealed the following themes corresponding to participants’ experiences and values in their social worlds of home, community, and schools: (a) martyrdom and self-sacrifice as a means for social justice; (b) transformational meaning of the Hijab; (c) intersectionality between culture, religion, and gender; and (d) effects of visits “back home” on participants’ religious identities. Additional themes related to participants’ school experiences included: (a) “us versus them” mentality; (b) religious and complex secular dialogues; (c) absence of Muslim representations in monocultural schools; (d) discrimination; (e) remaining silent versus speaking out; and (f) participants’ strategies for preserving their identities. Recommendations are made to integrate Shi’i Muslim females’ identity within the context of Islam and the West, most notably in relation to: (a) the role of Muslim community in nondiverse settings as a space that advances and nurtures Shi’i Muslim identity; and (b) holistic and culturally responsive teaching that fosters respect of others’ religiosity and spirituality. This study makes new inroads into feminist theorizing by drawing conceptual links between these previously unknown connections such as the impact of the historical female exemplary role model and the ritual stories on the experiences of Muslim females wearing the Hijab.