Siglec-7 (sialic acid–binding immunoglobulin-like lectin 7) is a glycan-binding immune receptor that is emerging as a significant target of interest for cancer immunotherapy. The physiological ...ligands that bind Siglec-7, however, remain incompletely defined. In this study, we characterized the expression of Siglec-7 ligands on peripheral immune cell subsets and assessed whether Siglec-7 functionally regulates interactions between immune cells. We found that disialyl core 1 O-glycans are the major immune ligands for Siglec-7 and that these ligands are particularly highly expressed on naïve T-cells. Densely glycosylated sialomucins are the primary carriers of these glycans, in particular a glycoform of the cell-surface marker CD43. Biosynthesis of Siglec-7-binding glycans is dynamically controlled on different immune cell subsets through a genetic circuit involving the glycosyltransferase GCNT1. Siglec-7 blockade was found to increase activation of both primary T-cells and antigen-presenting dendritic cells in vitro, indicating that Siglec-7 binds T-cell glycans to regulate intraimmune signaling. Finally, we present evidence that Siglec-7 directly activates signaling pathways in T-cells, suggesting a new biological function for this receptor. These studies conclusively demonstrate the existence of a novel Siglec-7-mediated signaling axis that physiologically regulates T-cell activity. Going forward, our findings have significant implications for the design and implementation of therapies targeting immunoregulatory Siglec receptors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Effective violence prevention interventions are largely inaccessible to trans women and trans femmes, despite clear evidence that disproportionate exposure to experiences of victimization is a social ...determinant of health disparity. Community-engaged implementation science paradigms hold promise for guiding research psychologists in the delivery of evidence-based programming to address drivers of health disparities impacting trans women and trans femmes. Unfortunately, guidance on how to engage in a process of real-time self-reflection to note where implementation is failing in its goals to establish reciprocal and sustainable (i.e., nonexploitative) community partnerships are lacking. We describe our application of a modified failure modes and effects analysis to guide data-informed adaptations to our community-engaged implementation research project, tailoring and delivering an evidence-based intervention to prevent victimization of trans women and trans femmes. By mapping our failure modes, we offer a blueprint for other research psychologists invested in advancing nonexploitative research in partnership with community.
Public Significance Statement
Community-engaged implementation research paradigms aim to expand the reach and impact of evidence-based programming to populations experiencing health disparities. However, few models exist for evaluating implementation of this research for health equity goals. In this article, we analyze modes of failure as a blueprint for researchers hoping to move their study processes toward nonexploitation.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
Ten organizations within the Electronic Medical Records and Genomics Network developed programs to implement pharmacogenomic sequencing and clinical decision support into clinical settings. ...Recognizing the importance of informed prescribers, a variety of strategies were used to incorporate provider education to support implementation. Education experiences with pharmacogenomics are described within the context of each organization's prior involvement, including the scope and scale of implementation specific to their Electronic Medical Records and Genomics projects. We describe common and distinct education strategies, provide exemplars and share challenges. Lessons learned inform future perspectives. Future pharmacogenomics clinical implementation initiatives need to include funding toward implementing provider education and evaluating outcomes.
This study examined short-term cardiac catheterization rates and medication changes after cardiac imaging.
Noninvasive cardiac imaging is widely used in coronary artery disease, but its effects on ...subsequent patient management are unclear.
We assessed the 90-day post-test rates of catheterization and medication changes in a prospective registry of 1,703 patients without a documented history of coronary artery disease and an intermediate to high likelihood of coronary artery disease undergoing cardiac single-photon emission computed tomography, positron emission tomography, or 64-slice coronary computed tomography angiography.
Baseline medication use was relatively infrequent. At 90 days, 9.6% of patients underwent catheterization. The rates of catheterization and medication changes increased in proportion to test abnormality findings. Among patients with the most severe test result findings, 38% to 61% were not referred to catheterization, 20% to 30% were not receiving aspirin, 35% to 44% were not receiving a beta-blocker, and 20% to 25% were not receiving a lipid-lowering agent at 90 days after the index test. Risk-adjusted analyses revealed that compared with stress single-photon emission computed tomography or positron emission tomography, changes in aspirin and lipid-lowering agent use was greater after computed tomography angiography, as was the 90-day catheterization referral rate in the setting of normal/nonobstructive and mildly abnormal test results.
Overall, noninvasive testing had only a modest impact on clinical management of patients referred for clinical testing. Although post-imaging use of cardiac catheterization and medical therapy increased in proportion to the degree of abnormality findings, the frequency of catheterization and medication change suggests possible undertreatment of higher risk patients. Patients were more likely to undergo cardiac catheterization after computed tomography angiography than after single-photon emission computed tomography or positron emission tomography after normal/nonobstructive and mildly abnormal study findings. (Study of Perfusion and Anatomy's Role in Coronary Artery CAD SPARC; NCT00321399).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Most current diagnostic tests for tuberculosis do not reveal the species or strain of pathogen causing pulmonary infection, which can lead to inappropriate treatment regimens and the spread of ...disease. Here, we report an assay for mycobacterial strain assignment based on genetically conserved mycobacterial sulfatases. We developed a sulfatase-activated probe, 7-hydroxy-9H-(1,3-dichloro-9,9-dimethylacridin-2-one)–sulfate, that detects enzyme activity in native protein gels, allowing the rapid detection of sulfatases in mycobacterial lysates. This assay revealed that mycobacterial strains have distinct sulfatase fingerprints that can be used to judge both the species and lineage. Our results demonstrate the potential of enzyme-activated probes for rapid pathogen discrimination for infectious diseases.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background The National Institute of Standards and Technology (NIST) Reference Material RM 8366 was developed to improve the quality of gene copy measurements of EGFR (epidermal growth factor ...receptor) and MET (proto-oncogene, receptor tyrosine kinase), important targets for cancer diagnostics and treatment. The reference material is composed of genomic DNA prepared from six human cancer cell lines with different levels of amplification of the target genes. Methods The reference values for the ratios of the EGFR and MET gene copy numbers to the copy numbers of reference genes were measured using digital PCR. The digital PCR measurements were confirmed by two additional laboratories. The samples were also characterized using Next Generation Sequencing (NGS) methods including whole genome sequencing (WGS) at three levels of coverage (approximately 1 ×, 5 × and greater than 30 ×), whole exome sequencing (WES), and two different pan-cancer gene panels. The WES data were analyzed using three different bioinformatic algorithms. Results The certified values (digital PCR) for EGFR and MET were in good agreement (within 20%) with the values obtained from the different NGS methods and algorithms for five of the six components; one component had lower NGS values. Conclusions This study shows that NIST RM 8366 is a valuable reference material to evaluate the performance of assays that assess EGFR and MET gene copy number measurements.
Highlights ► This feasibility study was not powered to find significant differences between groups. ► Parents were willing to receive text message reminders, but many had loss of cellular service at ...7-month follow-up. ► Per-protocol analysis of text reminders showed increased children receiving vaccines and receipt of vaccines on time; though not significant. ► Post intervention parents are highly supportive of text message reminders. ► A fully powered RCT is needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Most rare disease patients (75–50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information ...regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting. We developed RENEW, (REannotation of NEgative WES/WGS) an automated reannotation procedure that uses relevant new information in on-line genomic databases to enable rapid review of genomic findings. We tested RENEW in an unselected cohort of 1066 undiagnosed cases with a broad spectrum of phenotypes from the Mayo Clinic Center for Individualized Medicine using new information in ClinVar, HGMD and OMIM between the date of previous analysis/testing and April of 2022. 5741 variants prioritized by RENEW were rapidly reviewed by variant interpretation specialists. Mean analysis time was approximately 20 s per variant (32 h total time). Reviewed cases were classified as: 879 (93.0%) undiagnosed, 63 (6.6%) putatively diagnosed, and 4 (0.4%) definitively diagnosed. New strategies are needed to enable efficient review of genomic findings in unsolved cases. We report on a fast and practical approach to address this need and improve overall diagnostic success in patient testing through a recurrent reannotation process.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Water-soluble, highly fluorescent, silanized semiconductor nanocrystals with different surface charges were synthesized. To covalently attach the nanocrystals to biological macromolecules with a ...variety of mild coupling chemistries, the outermost siloxane shells were derivatized with thiol, amino, or carboxyl functional groups. Single- or double-stranded DNA was coupled to the nanocrystal surfaces by using commercially available bifunctional cross-linker. Conjugation had little effect on the optical properties of the nanocrystals, and the resulting conjugates were more stable than previously reported systems. By using the strategies developed in this study, most biomolecules can be covalently coupled to semiconductor nanocrystals. These nanocrystal-DNA conjugates promise to be a versatile tool for fluorescence imaging and probing of biological systems.
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IJS, KILJ, NUK, PNG, UL, UM
Mycobacteria contain high levels of the disaccharide trehalose in free form as well as within various immunologically relevant
glycolipids such as cord factor and sulfolipid-1. By contrast, most ...bacteria use trehalose solely as a general osmoprotectant
or thermoprotectant. Mycobacterium tuberculosis and Mycobacterium smegmatis possess three pathways for the synthesis of trehalose. Most bacteria possess only one trehalose biosynthesis pathway and
do not elaborate the disaccharide into more complex metabolites, suggesting a distinct role for trehalose in mycobacteria.
We disabled key enzymes required for each of the three pathways in M. smegmatis by allelic replacement. The resulting trehalose biosynthesis mutant was unable to proliferate and enter stationary phase
unless supplemented with trehalose. At elevated temperatures, however, the mutant was unable to proliferate even in the presence
of trehalose. Genetic complementation experiments showed that each of the three pathways was able to recover the mutant in
the absence of trehalose, even at elevated temperatures. From a panel of trehalose analogs, only those with the native α,α-(1,1)
anomeric stereochemistry rescued the mutant, whereas alternate stereoisomers and general osmo- and thermoprotectants were
inactive. These findings suggest a dual role for trehalose as both a thermoprotectant and a precursor of critical cell wall
metabolites.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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