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61.
Sandra Soo-Jin Lee Stephanie M. Fullerton Caitlin E. McMahon Michael Bentz Aliya Saperstein Melanie Jeske Emily Vasquez Nicole Foti Larissa Saco Janet K. Shim 《The Yale journal of biology and medicine》2022,95(3):317
Scientists have identified a “diversity gap” in genetic samples and health data, which have been drawn predominantly from individuals of European ancestry, as posing an existential threat to the promise of precision medicine. Inadequate inclusion as articulated by scientists, policymakers, and ethicists has prompted large-scale initiatives aimed at recruiting populations historically underrepresented in biomedical research. Despite explicit calls to increase diversity, the meaning of diversity – which dimensions matter for what outcomes and why – remain strikingly imprecise. Drawing on our document review and qualitative data from observations and interviews of funders and research teams involved in five precision medicine research (PMR) projects, we note that calls for increasing diversity often focus on “representation” as the goal of recruitment. The language of representation is used flexibly to refer to two objectives: achieving sufficient genetic variation across populations and including historically disenfranchised groups in research. We argue that these dual understandings of representation are more than rhetorical slippage, but rather allow for the contemporary collection of samples and data from marginalized populations to stand in as correcting historical exclusion of social groups towards addressing health inequity. We trace the unresolved historical debates over how and to what extent researchers should procure diversity in PMR and how they contributed to ongoing uncertainty about what axes of diversity matter and why. We argue that ambiguity in the meaning of representation at the outset of a study contributes to a lack of clear conceptualization of diversity downstream throughout subsequent phases of the study. 相似文献
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Bonacchi A Taddei ML Petrai I Efsen E Defranco R Nosi D Torcia M Rosini P Formigli L Rombouts K Zecchi S Milani S Pinzani M Laffi G Marra F 《Histology and histopathology》2008,23(3):327-340
The liver represents a site of expression of neurotrophins and their receptors. We have characterized the expression and intracellular localization of the nerve growth factor (NGF) receptor, Trk-A, in liver cells in vivo and in vitro. In both normal and fibrotic liver tissue, Trk-A immunostaining was present in different cell types, including parenchymal cells and cells of the inflammatory infiltrate. In hepatocytes and activated stellate cells (HSC), Trk-A showed a predominant nuclear localization, both in the presence and absence of injury. In cultured HSC, Trk-A was found to be functional, because exposure of the cells to recombinant NGF resulted in stimulation of cell migration and activation of intracellular signaling pathways, including Ras-ERK and PI3K/Akt. Remarkably, in cultured HSC, Trk-A staining was found constitutively in the nucleus. In these cells, Trk-A could be stained only by antibodies directed against the intracellular domain but not by those recognizing the extracellular portion of Trk-A suggesting that the intracellular portion of the receptor is the major determinant of nuclear Trk-A staining. In contrast to HSC, freshly isolated hepatocytes did not show any nuclear localization of the intracellular portion of Trk-A. In pheocromocytoma cells, nuclear staining for Trk-A was not present in conditions of serum deprivation, but could be induced by exposure to NGF or to a mixture of soluble mediators. We conclude that nuclear localization of the intracellular domain of Trk-A is observed constitutively in liver cells such as HSC, while in other cell types it could be induced in response to soluble factors. 相似文献
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65.
Van Bergen NJ Crowston JG Kearns LS Staffieri SE Hewitt AW Cohn AC Mackey DA Trounce IA 《PloS one》2011,6(6):e21347
Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies. 相似文献
66.
ABSTRACTIn 2016, the Gerontological Society of America (GSA) developed a research focus on the benefits and potential risks associated with pets among older adults. With the goal of developing a roadmap for human–animal interaction (HAI) research in older people residing in both the community and institutions, GSA convened a workshop of international experts and policy-makers in the fields of aging and HAI. The status of current knowledge was shared on the success factors for healthy aging and the potential challenges (GSA, 2016). Participants considered what roles pets might play in the lives of older adults and their potential to mitigate loneliness, social isolation, and depression, and to enhance mobility and cognitive function. Existing research was shared to provide insights into the ways in which pets can impact older adults and their caregivers and to identify where further research is needed. This paper introduces a series of papers from that meeting, with some additional papers from meeting attendees to expand on the topics covered and provide key perspectives and gaps in information needed, as a foundation for those considering research into this topic. Although HAI/Animal-Assistant Intervention (AAI) research is in its infancy, there is some evidence that pet ownership or animal interaction can have major benefits for many older adults. At the same time, there are some risks to both the pet and the older adult that need to be addressed. Innovative approaches to both AAIs and the ways to overcome challenges are presented in this themed issue of Anthrozoös. Our hope is that the findings from these reviews and reports will stimulate additional work in this area. 相似文献
67.
The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor 总被引:14,自引:0,他引:14
Tjabringa GS Aarbiou J Ninaber DK Drijfhout JW Sørensen OE Borregaard N Rabe KF Hiemstra PS 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(12):6690-6696
Antimicrobial peptides produced by epithelial cells and neutrophils represent essential elements of innate immunity, and include the defensin and cathelicidin family of antimicrobial polypeptides. The human cathelicidin cationic antimicrobial protein-18 is an antimicrobial peptide precursor predominantly expressed in neutrophils, and its active peptide LL-37 is released from the precursor through the action of neutrophil serine proteinases. LL-37 has been shown to display antimicrobial activity against a broad spectrum of microorganisms, to neutralize LPS bioactivity, and to chemoattract neutrophils, monocytes, mast cells, and T cells. In this study we show that LL-37 activates airway epithelial cells as demonstrated by activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and increased release of IL-8. Epithelial cell activation was inhibited by the MAPK/ERK kinase (MEK) inhibitors PD98059 and U0126, by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478, by blocking anti-EGFR and anti-EGFR-ligand Abs, and by the metalloproteinase inhibitor GM6001. These data suggest that LL-37 transactivates the EGFR via metalloproteinase-mediated cleavage of membrane-anchored EGFR-ligands. LL-37 may thus constitute one of the mediators by which neutrophils regulate epithelial cell activity in the lung. 相似文献
68.
69.
Nelson H. Koshoji Sandra K. Bussadori Carolina C. Bortoletto Renato A. Prates Marcelo T. Oliveira Alessandro M. Deana 《PloS one》2015,10(2)
Erosion is a highly prevalent condition known as a non-carious lesion that causes progressive tooth wear due to chemical processes that do not involve the action of bacteria. Speckle images proved sensitive to even minimal mineral loss from the enamel. The aim of the present study was to investigate the use of laser speckle imaging analysis in the spatial domain to quantify shifts in the microstructure of the tooth surface in an erosion model. 32 fragments of the vestibular surface of bovine incisors were divided in for groups (10 min, 20 min. 30 min and 40 min of acid etching) immersed in a cola-based beverage (pH approximately 2.5) twice a day during 7 days to create an artificial erosion. By analyzing the laser speckle contrast map (LASCA) in the eroded region compared to the sound it was observed that the LASCA map shifts, proportionally to the acid each duration, by: 18%; 23%; 39% and 44% for the 10 min; 20 min; 30 min and 40 min groups, respectively. To the best of our knowledge, this is the first study to demonstrate the correlation between speckle patterns and erosion progression. 相似文献
70.
SIV DNA vaccine co-administered with IL-12 expression plasmid enhances CD8 SIV cellular immune responses in cynomolgus macaques 总被引:5,自引:0,他引:5
Boyer JD Robinson TM Kutzler MA Parkinson R Calarota SA Sidhu MK Muthumani K Lewis M Pavlakis G Felber B Weiner D 《Journal of medical primatology》2005,34(5-6):262-270
Current evidence suggests that a strong induced CD8 human immunodeficiency virus type 1 (HIV-1)-specific cell mediated immune response may be an important aspect of an HIV vaccine. The response rates and the magnitude of the CTL responses induced by current DNA vaccines in humans need to be improved and cellular immune responses to DNA vaccines can be enhanced in mice by co-delivering DNA plasmids expressing immune modulators. Two reported to work well in the mouse systems are interleukin (IL)-12 and CD40L. We sought to compare these molecular adjuvants in a primate model system. The cDNA for macaque IL-12 and CD40L were cloned into DNA vectors. Groups of cynomolgus macaques were immunized with 2 mg of plasmid expressing SIVgag alone or in combination with either IL-12 or CD40L. CD40L did not appear to enhance the cellular immune response to SIVgag antigen. However, more robust results were observed in animals co-injected with the IL-12 molecular adjuvant. The IL-12 expanded antigen-specific IFN-gamma positive effector cells as well as granzyme B production. The vaccine immune responses contained both a CD8 component as well a CD4 component. The adjuvanted DNA vaccines illustrate that IL-12 enhances a CD8 vaccine immune response, however, different cellular profiles. 相似文献