153 results on '"Logan, C."'
Search Results
2. Affinity Constants of Bovine Serum Albumin for 5 nm Gold Nanoparticles (AuNPs) with ω-Functionalized Thiol Monolayers Determined by Fluorescence Spectroscopy.
- Author
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Hanigan-Diebel, Jennifer L., Costin, Robert J., Myers, Logan C., Vandermeer, Christopher I., Willis, Miles S., Takhar, Kiran, Odinakachukwu, Ogechukwu V., Carroll, Matthias G., Schiffbauer, Jarrod E., and Lohse, Samuel E.
- Published
- 2024
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3. Tianeptine, an Antidepressant with Opioid Agonist Effects: Pharmacology and Abuse Potential, a Narrative Review.
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Edinoff, Amber N., Sall, Saveen, Beckman, Scott P., Koepnick, Andrew D., Gold, Logan C., Jackson, Eric D., Wenger, Danielle M., Cornett, Elyse M., Murnane, Kevin S., Kaye, Adam M., and Kaye, Alan D.
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- 2023
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4. Instability after reverse shoulder arthroplasty with tendon transfer: a case series.
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Kolakowski, Logan C., Livesey, Michael G., Hasan, S. Ashfaq, Horneff III, John Gabriel, Sykes, Joshua B., Gilotra, Mohit N., and Levy, Jonathan C.
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RESEARCH ,JOINT instability ,REVERSE total shoulder replacement ,SURGICAL complications ,RETROSPECTIVE studies ,HEMIARTHROPLASTY ,T-test (Statistics) ,LATISSIMUS dorsi (Muscles) ,DESCRIPTIVE statistics ,CHI-squared test ,CASE studies ,BODY mass index ,ROTATOR cuff - Abstract
Reverse shoulder arthroplasty with tendon transfer (RSA-TT) was introduced by Boileau for patients with rotator cuff arthropathy and combined loss of active elevation and external rotation. TT at the time of RSA has been shown to increase external rotation compared to RSA alone. Postoperative instability following RSA-TT is thought to be an uncommon complication reported in around 5% of cases. We present a novel case series of RSA-TT and postoperative instability. A multicenter retrospective review was performed identifying patients who underwent RSA-TT between 2008 and 2021. Patients with rotator cuff arthropathy and combined loss of active elevation and external rotation undergoing RSA-TT and aged more than 18 years were included. Revision arthroplasty cases were excluded. Implants and TT technique were selected by the treating surgeon. Patient demographics, surgical data, and postoperative metrics were collected. Continuous variables were calculated as mean and standard deviation and then compared using Student's t -test. Frequencies and proportions were calculated for categorical variables and compared using Chi-squared test. Thirty-one patients underwent RSA-TT; 21 patients had sufficient follow-up for analysis. Seven patients (25%) had a postoperative dislocation event. Patients with instability were male with average age of 70 ± 6 years and body mass index 29 ± 4 kg/m
2 . The latissimus dorsi was transferred in all patients with teres major additionally transferred in 2 patients. Subscapularis was repaired in 4 patients, irreparable in 1 patient, and voluntarily not repaired in 2 patients. All dislocation events were anterior and spontaneous without inciting traumatic event. Three patients dislocated within 2 weeks of surgery. Three patients dislocated 1-2 months postoperatively. One patient dislocated nearly 6 months following surgery. At time of revision surgery, TT was intact in all patients. Two patients required multiple revision procedures to attain definitive stability, including one conversion to hemiarthroplasty. The TTs were taken down in 3 patients. At final follow-up, all patients remained stable. There were no documented nerve palsies. Final range of motion for patients with and without instability did not significantly differ. The series suggests that postoperative instability following RSA-TT is more common than previously reported. Despite instability requiring surgical revision, final range of motion did not significantly differ between those with stable and unstable RSA-TT patients. In those who suffered an instability event, dislocation occurred within 2 months of surgery in 86% of cases. It is important to be aware of this elevated risk of instability following this procedure and to tailor rehabilitation protocols accordingly. [ABSTRACT FROM AUTHOR]- Published
- 2023
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5. Relationships between neuroimaging parameters, APOE genotypes and composite scores for memory, executive functioning and language from the National Alzheimer's Coordinating Center (NACC).
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Lee, Michael L., Scollard, Phoebe, Gibbons, Laura E, Mukherjee, Shubhabrata, Choi, Seo‐Eun, Klinedinst, Brandon S, Trittschuh, Emily H., Mez, Jesse B., Saykin, Andrew J., Dumitrescu, Logan C, Kukull, Walter A., Hohman, Timothy J., and Crane, Paul K
- Abstract
Background: We harmonized composite scores for memory, executive functioning (EF), and language from granular cognitive data from the National Alzheimer's Coordinating Center (NACC) uniform dataset on 39,965 individuals. We explored if our cognitive scores correlated with APOE genotype and structural magnetic resonance imaging data. Method: In our previously published harmonization methods we used confirmatory factor analysis models, guided by theoretical considerations from content experts, to estimate domain scores. For this cross‐sectional analysis of last visits in participants over age 60, we obtained APOE genotype data (n = 28,558 individuals) and FreeSurfer regional volume data (n = 2,404 individuals). We looked at relationship between cognitive performance and APOE genotype grouping by disease group (normal cognition, mild cognitive impairment (MCI), or AD dementia). We ran student's two sample t‐test to assess the effect of APOE ε4 genotype on cognitive domain score. We also ran regression models for cognitive domain scores on each FreeSurfer region selected a priori on the basis of assumed association on that index domain adjusting for age, gender and APOE genotype. Result: Relevant demographic and clinical data are summarized in Table 1. Associations with APOE genotype and each cognitive domain are shown in Figure 1. As expected, participants with at least one APOE ε4 alleles compared with none had lower composite memory scores (p<0.01, t‐test) compared with those with none in participants with dementia and MCI. APOE ε4 carriers also had lower language scores in participants with dementia (p = 0.037, t‐test). Among the FreeSurfer regions, composite memory scores were strongly associated with hippocampal volume, parahippocampus and entorhinal cortex thickness across all dementia categories (Table 2). EF scores were associated with 2 EF brain regions of interest in participants with dementia. Language scores were associated with 2 language regions of interest in participants with dementia. Conclusion: Our analyses shows composite scores are associated with APOE genotype in participants with dementia and relevant brain regions in the memory domain across all dementia categories. Our analyses shows that our cognitive scores correlate with memory brain regions and APOE genotype in expected directions. [ABSTRACT FROM AUTHOR]
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- 2023
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6. Region‐Specific Associations of Human Astrocytic Endfoot Genes with Alzheimer's Disease Neuropathology and Cognitive Decline.
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Phillips, Jared, Seto, Mabel, Winfree, Rebecca L, Wang, Yanling, Schneider, Julie A, Bennett, David A. A, Dumitrescu, Logan C, and Hohman, Timothy J.
- Abstract
Background: We completed a well‐powered bulk transcriptomic analysis of the astrocytic water channel aquaporin‐4 (AQP4) and related glymphatic molecules and discovered significant associations with Alzheimer's disease (AD) neuropathological and cognitive outcomes. Genes included AQP4 and dystrophin‐associated complex components, namely DMD, DTNA, DAG1, and SNTA1, which encode proteins responsible for anchoring the AQP4 channel to the astrocytic endfoot membrane. Method: Leveraging regional brain RNA sequencing from the ROS/MAP dataset (Table 1), we determined the effects of transcript‐level variation on neuropathological outcomes at autopsy and longitudinal cognition using multiple linear regression models and mixed effects models, respectively. Discrete brain regions included: the dorsolateral prefrontal cortex (DLPFC, N = 921), caudate nucleus (CN, N = 705), and posterior cingulate cortex (PCC, N = 516). Square‐root transformed neuropathological measures of amyloid and tau burden at autopsy were quantified using immunohistochemistry. Cognitive performance was assessed longitudinally with global cognition calculated as a composite score derived from 19 neuropsychological tests. All model covariates included age at death, sex, educational attainment, and post‐mortem interval. Longitudinal models also included latency to death and the fixed and random effect of interval between current and last visit. Result: Higher AQP4 expression in the DLPFC related to higher amyloid pathology (β = 0.21, P.fdr = 0.04). Similarly, higher DTNA expression was associated with higher tau burden (βDLPFC = 0.36, P.fdrDLPFC = 0.008) and a faster rate of cognitive decline (βDLPFC = ‐0.036, P.fdrDLPFC = 0.0004; βPCC = ‐0.037, P.fdrPCC = 0.02). Higher SNTA1 in the CN related to a faster rate of cognitive decline (β = ‐0.038, P.fdr = 0.03). A summary of significant associations is presented in Table 2 and select plots are provided in Figure 2. AQP4, DTNA, and SNTA1 showed comparable associations with clinical AD in independent datasets within the AMP‐AD project (https://agora.adknowledgeportal.org/). Conclusion: Our results indicate that gene expression at the AQP4‐dystrophin axis relates to both AD neuropathology and cognition, particularly in the prefrontal cortex. Future analyses will incorporate single‐nucleus measures of gene expression and cell‐type deconvolution to clarify cell‐type specific contributions in this pathway. Together, these results highlight a set of genes relevant to glymphatic function that should be prioritized for future mechanistic studies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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7. Sex‐specific associations of gene expression in brain with Alzheimer's disease pathology and cognitive performance.
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Clifton, Michelle, Seto, Mabel, Buckley, Rachel F., Gifford, Katherine A., Jefferson, Angela L., De Jager, Philip L, Bennett, David A. A, Barnes, Lisa L., Wang, Yanling, Schneider, Julie A, Hohman, Timothy J., and Dumitrescu, Logan C
- Abstract
Background: Alzheimer's disease (AD) disproportionately affects women, who make up two‐thirds of all clinical cases of AD. While sex differences in AD neuropathology, the response to pathology, and the genetic predictors of clinical AD have been well described, sex differences in the brain transcriptomic signatures of AD endophenotypes have not been fully characterized. Methods: We leveraged bulk RNA‐sequencing data from three brain regions (dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex, and caudate nucleus from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). Propensity scoring was used to match male to female participants due to disproportionate sample size. As a result, there were 791 participants (50% male; mean age at death = 87.6 years). Sex‐stratified and sex‐interaction (int) regression models assessed sex‐specific transcript associations with amyloid and tau burden, along with longitudinal global cognition. Age at death, latency to death, and post‐mortem interval were included as covariates. Sex‐specific genes were defined as related to a trait in one sex (FDR‐corrected P<0.05) but not in the other sex and that showed evidence of a sex‐modifying effect (Pint<0.05). Results: Of the more than 20,000 significant autosomal gene expression associations with the three AD endophenotypes, 11% were sex‐specific with DLPFC having largest number of sex‐specific genes (7%). Despite equivalent percentages of males and females, we observed more female‐specific effects (10%) than male‐specific effects (1%) (Figure 1). Several genes showed particularly strong effects among females, including LRIG3 with amyloid (Pmen = 0.20, Pwomen = 3.34×10−06, Pint = 0.017) and tau tangles (Pmen = 0.34, Pwomen = 0.008, Pint = 0.008), and SLC22A17 with amyloid (Pmen = 0.8, Pwomen = 1.63×10−04, Pint = 0.02) and tau tangles (Pmen = 0.18, Pwomen = 4.81×10−05, Pint = 0.04). There were 16 genes with male‐specific associations with at least two traits including FAIM2 (Pmen = 9.9×10−4, Pwomen = 0.49, Pint = 0.004), ATP13A2 (Pmen = 8.3×10−5, Pwomen = 0.68, Pint = 0.002), and PRSS35 (Pmen = 7.5×10−5, Pwomen = 0.64, Pint = 0.02) (Figure 2). Conclusion: Our results highlight sex‐specific transcriptomic associations with AD endophenotypes, including genes for protein misfolding and neurotrophic signaling among females and for neuron apoptotic involvement among males. Similar sex‐specific patterns with AD were observed in independent AMP‐AD cohorts for LRIG3, SLC22A17, and FAIM2 (https://agora.adknowledgeportal.org/).These findings highlight the exciting potential of precision medicine approaches that consider sex‐specific biological pathways to select new targets for mechanistic evaluation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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8. Sex‐specific associations of gene expression in brain with Alzheimer's disease pathology and cognitive performance.
- Author
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Clifton, Michelle, Seto, Mabel, Buckley, Rachel F., Gifford, Katherine A., Jefferson, Angela L., De Jager, Philip L, Bennett, David A. A, Barnes, Lisa L., Wang, Yanling, Schneider, Julie A, Hohman, Timothy J., and Dumitrescu, Logan C
- Abstract
Background: Alzheimer's disease (AD) disproportionately affects women, who make up two‐thirds of all clinical cases of AD. While sex differences in AD neuropathology, the response to pathology, and the genetic predictors of clinical AD have been well described, sex differences in the brain transcriptomic signatures of AD endophenotypes have not been fully characterized. Methods: We leveraged bulk RNA‐sequencing data from three brain regions (dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex, and caudate nucleus from the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP). Propensity scoring was used to match male to female participants due to disproportionate sample size. As a result, there were 791 participants (50% male; mean age at death = 87.6 years). Sex‐stratified and sex‐interaction (int) regression models assessed sex‐specific transcript associations with amyloid and tau burden, along with longitudinal global cognition. Age at death, latency to death, and post‐mortem interval were included as covariates. Sex‐specific genes were defined as related to a trait in one sex (FDR‐corrected P<0.05) but not in the other sex and that showed evidence of a sex‐modifying effect (Pint<0.05). Results: Of the more than 20,000 significant autosomal gene expression associations with the three AD endophenotypes, 11% were sex‐specific with DLPFC having largest number of sex‐specific genes (7%). Despite equivalent percentages of males and females, we observed more female‐specific effects (10%) than male‐specific effects (1%) (Figure 1). Several genes showed particularly strong effects among females, including LRIG3 with amyloid (Pmen = 0.20, Pwomen = 3.34×10−06, Pint = 0.017) and tau tangles (Pmen = 0.34, Pwomen = 0.008, Pint = 0.008), and SLC22A17 with amyloid (Pmen = 0.8, Pwomen = 1.63×10−04, Pint = 0.02) and tau tangles (Pmen = 0.18, Pwomen = 4.81×10−05, Pint = 0.04). There were 16 genes with male‐specific associations with at least two traits including FAIM2 (Pmen = 9.9×10−4, Pwomen = 0.49, Pint = 0.004), ATP13A2 (Pmen = 8.3×10−5, Pwomen = 0.68, Pint = 0.002), and PRSS35 (Pmen = 7.5×10−5, Pwomen = 0.64, Pint = 0.02) (Figure 2). Conclusion: Our results highlight sex‐specific transcriptomic associations with AD endophenotypes, including genes for protein misfolding and neurotrophic signaling among females and for neuron apoptotic involvement among males. Similar sex‐specific patterns with AD were observed in independent AMP‐AD cohorts for LRIG3, SLC22A17, and FAIM2 (https://agora.adknowledgeportal.org/).These findings highlight the exciting potential of precision medicine approaches that consider sex‐specific biological pathways to select new targets for mechanistic evaluation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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9. Role of Air Pollution in the Development of Asthma Among Children with a History of Bronchiolitis in Infancy.
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Dearborn, Logan C., Hazlehurst, Marnie F., Loftus, Christine T., Szpiro, Adam A., Carroll, Kecia N., Moore, Paul E., Adgent, Margaret A., Barrett, Emily S., Nguyen, Ruby H. N., Sathyanarayana, Sheela, LeWinn, Kaja Z., Bush, Nicole R., Kaufman, Joel D., and Karr, Catherine J.
- Abstract
Background: Infants experiencing bronchiolitis are at increased risk for asthma, but few studies have identified modifiable risk factors. We assessed whether early life air pollution influenced child asthma and wheeze at age 4-6 years among children with a history of bronchiolitis in the first postnatal year. Methods: Children with caregiver-reported physician-diagnosed bronchiolitis were drawn from ECHO-PATHWAYS, a pooled longitudinal cohort from six US cities. We estimated their air pollution exposure from age 1 to 3 years from validated spatiotemporal models of fine particulate matter (PM
2.5 ), nitrogen dioxide (NO2 ), and ozone (O3 ). Caregivers reported children's current wheeze and asthma at age 4-6 years. We used modified Poisson regression to estimate relative risks (RR) and 95% confidence intervals (CI), adjusting for child, maternal, and home environmental factors. We assessed effect modification by child sex and maternal history of asthma with interaction models. Results: A total of 224 children had caregiver-reported bronchiolitis. Median (interquartile range) 2-year pollutant concentrations were 9.3 (7.8-9.9) µg/m3 PM2.5, 8.5 (6.4-9.9) ppb NO2 , and 26.6 (25.6-27.7) ppb O3 . RRs (CI) for current wheeze per 2-ppb higher O3 were 1.3 (1.0-1.7) and 1.4 (1.1-1.8) for asthma. NO2 was inversely associated with wheeze and asthma whereas associations with PM2.5 were null. We observed interactions between NO2 and PM2.5 and maternal history of asthma, with lower risks observed among children with a maternal history of asthma. Conclusion: Our results are consistent with the hypothesis that exposure to modest postnatal O3 concentrations increases the risk of asthma and wheeze among the vulnerable subpopulation of infants experiencing bronchiolitis. [ABSTRACT FROM AUTHOR]- Published
- 2023
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10. Not So Clear and Plain: Exploring the Circuit Split on the Applicability of Federal Labor & Employment Laws to Tribes.
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Hibbs, Logan C.
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LABOR laws ,TRIBES ,TRIBAL sovereignty ,FAIR Labor Standards Act of 1938 (U.S.) ,NATIONAL Labor Relations Act (U.S.) ,UNITED States. Age Discrimination in Employment Act of 1967 ,UNITED States. Occupational Safety & Health Act of 1970 - Published
- 2023
11. Does needle penetration of the shoulder joint prior to arthroscopy increase infection risk? The effect of preoperative magnetic resonance arthrogram or corticosteroid injection.
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Livesey, Michael G., Bains, Sandeep S., Weir, Tristan B., Kolakowski, Logan C., Remily, Ethan A., Sax, Oliver C., Gilotra, Mohit N., and Hasan, S. Ashfaq
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Prior literature has associated preoperative corticosteroid shoulder injection (CSI) with infection following shoulder surgery. A recent study found an equally elevated risk of total knee arthroplasty infection with preoperative injection of either CSI or hyaluronic acid. The implication is that violation of a joint prior to surgery, even in the absence of corticosteroid, may pose an elevated risk of infection following orthopedic surgery. The aim of the present study was to determine whether violation of the shoulder joint for magnetic resonance arthrogram (MRA) poses an elevated risk of infection following shoulder arthroscopy, and to compare this risk to that introduced by preoperative CSI. A national, all-payer database was queried to identify patients undergoing shoulder arthroscopy between January 2015 and October 2020. Patients were stratified into the following groups: (1) no CSI or MRA within 6 months of surgery (n = 5000), (2) CSI within 2 weeks of surgery (n = 1055), (3) CSI between 2 and 4 weeks prior to surgery (n = 2575), (4) MRA within 2 weeks of surgery (n = 414), and (5) MRA between 2 and 4 weeks prior to surgery (n = 1138). Postoperative infection (septic shoulder or surgical site infection) was analyzed at 90 days, 1 year, and 2 years, postoperatively. Multivariable logistic regression analysis controlled for differences among groups. MRA within 2 weeks prior to shoulder surgery was associated with an increased risk of infection at 1 year (odds ratio [OR], 2.17; P =.007), while MRA 2-4 weeks preceding surgery was not associated with an increased risk of postoperative infection at any time point. By comparison, CSI within 2 weeks prior to surgery was associated with an increased risk of postoperative infection at 90 days (OR, 1.72; P =.022), 1 year (OR, 1.65; P =.005), and 2 years (OR, 1.63; P =.002) following surgery. Similarly, CSI 2-4 weeks prior to surgery was associated with an increased risk of postoperative infection at 90 days (OR, 1.83; P <.001), 1 year (OR, 1.62; P <.001), and 2 years (OR, 1.79; P <.001). Preoperative CSI within 4 weeks of shoulder arthroscopy elevates the risk of postoperative infection. Needle arthrotomy for shoulder MRA elevates the risk of infection in a more limited fashion. Avoidance of MRA within 2 weeks of shoulder arthroscopy may mitigate postoperative infection risk. Additionally, the association between preoperative CSI and postoperative infection may be more attributed to medication profile than to needle arthrotomy. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Role of Air Pollution in the Development of Asthma Among Children with a History of Bronchiolitis in Infancy
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Dearborn, Logan C, Hazlehurst, Marnie F, Loftus, Christine T, Szpiro, Adam A, Carroll, Kecia N, Moore, Paul E, Adgent, Margaret A, Barrett, Emily S, Nguyen, Ruby HN, Sathyanarayana, Sheela, LeWinn, Kaja Z, Bush, Nicole R, Kaufman, Joel D, and Karr, Catherine J
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- 2023
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13. Tianeptine, an Antidepressant with Opioid Agonist Effects: Pharmacology and Abuse Potential, a Narrative Review
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Edinoff, Amber N., Sall, Saveen, Beckman, Scott P., Koepnick, Andrew D., Gold, Logan C., Jackson, Eric D., Wenger, Danielle M., Cornett, Elyse M., Murnane, Kevin S., Kaye, Adam M., and Kaye, Alan D.
- Abstract
Tianeptine is an antidepressant drug approved for the treatment of major depressive disorder in countries other than the US. It is classified as an atypical tricyclic antidepressant and has shown potential benefits in addressing anxiety and irritable bowel disease. However, it is important to note that tianeptine is not approved for any use by the United States Federal Drug Administration (FDA). Despite its lack of approval by the FDA, tianeptine has been distributed online and at small retail locations. The term “gas station drugs” refers to a wide range of substances typically available for purchase from gas stations, corner stores, bodegas, mini marts, smoke shops, and the Internet. These substances may be produced commercially by drug manufacturers or in clandestine laboratories to mimic the effects of more well-known illicit/controlled substances such as marijuana, cocaine, opioids, etc. Tianeptine has made its way to convenience stores and gas station shelves, branded as “Zaza” and “Tianna Red.” It can also be obtained online from independent vendors without a prescription. Misuse of tianeptine can lead to euphoric, opioid-like highs with the potential for chronic users to develop dependence and tolerance. Overdose and use in suicide attempts have also been documented. This manuscript is a narrative review, highlighting the dangers of tianeptine and other gas station drugs and underscoring the urgent need to regulate these substances.
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- 2023
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14. Multi‐cohort genome‐wide association study on flortaucipir PET identifies novel risk loci associated with tau deposition and its role in AD pathology.
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Gunasekaran, Tamil Iniyan, Lee, Annie J, Dumitrescu, Logan C, Mormino, Elizabeth C., Sperling, Reisa A., Saykin, Andrew J., Hohman, Timothy J., and Vardarajan, Badri N
- Abstract
Background: Amyloid‐β plaques and tau neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease (AD). Previously, genetic studies on amyloid‐β mediated AD pathogenesis dominated the field, and genetic studies on tau pathology are limited by comparison. Prior studies suggest that the spread of tau neurofibrillary tangles within the medial temporal lobe occurs following abnormal deposition of amyloid‐β, leading to cognitive impairment. Although amyloid‐β and tau both play a role in AD pathogenesis, exact genetic pathways associated with them are still unknown. Method: We performed genome‐wide association study (GWAS) with brain Tau standard uptake value ratios (SUVRs) measured from positron emission tomography (PET) images from the A4 ((N = 311 with preclinical AD;female = 62%;tau mean‐SUVR = 1.076±0.06) and ADNI studies (N = 375‐280 cognitively normal, 76 mild cognitively impaired and 19 AD;female = 53%;tau mean‐SUVR = 1.12±0.13). Models were adjusted for age, sex and APOE‐ε4 dosage. Additionally, we evaluated the association of amyloid‐β and tau SUVRs with AD polygenic risk scores (PRS). PRS was calculated using genome‐wide variants, excluding 1MB region flanking APOE, and effect sizes from Kunkle et al GWAS study of clinical AD. Result: Analysis of tau‐SUVR in 686 participants, identified five genome‐wide significant loci: rs78636169 (P = 1.37×10−9) in JARID2, rs114272033 (P = 7.87×10−9) in ISCA1P2, rs7292124 (P = 1.73×10−8) in RP1‐272J12.1, rs114742337 (P = 2.85×10−8) in RP4‐771M4.2, and rs138338441 (P = 3.91×10−8) in AC092684.1. Rs13412014 in AC007364.1 and rs9393067 in RP11‐314C16.1 were also associated with amyloid‐SUVR in a previous large GWAS. Two loci previously associated with clinical AD in a recent large GWA study, INPP5D (rs10933431) and SEC61G (rs76928645), were also nominally associated (P<0.05) with tau deposition in our study. Genes associated with Tau‐SUVR are enriched in the Schaffer axonal collaterals (P<1×10−05) that form synapses in hippocampus. Genome‐wide PRS of AD (excluding APOE region) was strongly associated with amyloid‐SUVR (P = 3.21×10−11;R2 = 0.077) but only weakly associated with tau‐SUVR (P = 1.38×10−04;R2 = 0.027). We are in the process of replicating our results in an independent cohort of 700 participants with measurements of tau deposition. Conclusion: We identified five novel genetic loci associated with tau pathology. Several genes involved in tau deposition were also associated with amyloid load in the brain. Taken together, our findings will clarify the genetic pathways that effect both amyloid and tau pathology in AD. [ABSTRACT FROM AUTHOR]
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- 2023
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15. Discovery‐based proteomics identifies plasma proteins that predict longitudinal cognitive decline in older adults over a 7‐year follow‐up period.
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Kresge, Hailey A., Patterson, Khiry L, Libby, Julia B., Robb, W Hudson, Arul, Albert B, Choi, Min Ji, Oliver, Nekesa, Whitaker, Marsalas D, Moore, Elizabeth E., Houston, Michelle L, Pechman, Kimberly R., Dumitrescu, Logan C, Gifford, Katherine A., Hohman, Timothy J., Robinson, Renã AS, and Jefferson, Angela L.
- Abstract
Background: Recent technological advances have enabled large‐scale proteomic profiling of plasma and especially in studies of Alzheimer's disease. However, studies that have comprehensively examined longitudinal cognitive decline as an outcome from plasma protein levels prior to the onset of clinical dementia are limited. This project aimed to identify plasma proteins predictive of cognitive decline across a robust neuropsychological protocol over a 7‐year follow‐up period. Methods: Vanderbilt Memory and Aging Project participants (n = 333, 73±7 years, 41% female) free of clinical dementia at study entry underwent fasting blood draw and comprehensive serial neuropsychological assessment over a 7‐year period (mean follow‐up = 5.8 years). Plasma samples were subjected to multiplex liquid chromatography tandem mass spectrometry analysis to quantify cross‐sectional protein abundances for each participant at study entry. Normalization of proteomic data adjusted for batch effects, high levels of missingness, and log2 transformation. Linear mixed‐effects regressions related protein levels to longitudinal neuropsychological outcomes, adjusting for age, sex, race/ethnicity, education, baseline cognitive status, apolipoprotein E ε4 status, and follow‐up time. False discovery rate correction was applied to the a priori significance threshold. Results: Initial proteomics analyses yielded 3,784 proteins, of which 686 were used as analytical predictors following quality control, post‐acquisition filtering, and data normalization. Regression analyses resulted in 86 proteins which predicted longitudinal decline in global cognition, as assessed by the Montreal Cognitive Assessment. In analyses with individual neuropsychological domains as outcomes, 144 proteins predicted longitudinal decline in at least one neuropsychological domain [episodic memory (40 proteins), language (72 proteins), information processing speed (99 proteins), executive function (22 proteins), visuospatial skills (55 proteins)]. There was a smaller number of proteins (i.e., five) that were predictive of longitudinal cognitive decline across all domains. Conclusion: We conducted large‐scale proteomics analyses and identified 144 plasma proteins at study entry among a cohort of older adults free of clinical dementia that predict subsequent decline in cognition over a 7‐year follow‐up period. Five of these proteins were predictive of decline across all domains suggesting these proteins may represent biological pathways that adversely affect brain health with increasing age. Replication is needed to validate identified proteins as potential biomarkers of cognitive decline. [ABSTRACT FROM AUTHOR]
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- 2023
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16. Genetically Regulated Telomere Length Relates to Brain Amyloidosis.
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Libby, Julia B., Roshani, Rashedeh, Seto, Mabel, Wang, Ting‐Chen, Nudelman, Kelly N. H., Buckley, Rachel F., Saykin, Andrew J., Mormino, Elizabeth C., Sperling, Reisa A., Mayeux, Richard, Dumitrescu, Logan C, and Hohman, Timothy J.
- Abstract
Background: It is well‐established that telomeres shrink over the course of aging and that this process is genetically regulated. Work from our group and others has highlighted the complex interplay between measured leukocyte telomere length and Alzheimer's Disease (AD) biomarkers over the course of AD. We expand on this work to explore whether a polygenic score predicting telomere length relates to PET measures of brain amyloidosis in the preclinical stages of disease. Method: A Polygenic Risk Score (PRS) of telomere length was built from a published GWAS on telomere length from UK Biobank (N = 472,174). We leveraged genetic data from non‐Hispanic White participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1,414) and the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's study (A4; N = 3,002). The relation of the score to measured telomere length was validated using leukocyte telomere length data from ADNI. A linear regression model was used to evaluate whether the PRS relates to a PET measure of brain amyloidosis in a harmonized dataset including ADNI and A4, with a total sample size of 3,940 after restricting to individuals with both genetic data and amyloid measurements. Covariates included age, sex, and diagnostic status. Result: As expected, telomere PRS related to measured telomeres in ADNI when covarying for age, sex, and baseline diagnosis (Figure 1, p = 0.045). Interestingly, we also observed a counter intuitive association between genetically predicted telomere length and amyloidosis whereby longer predicted telomere length was associated with higher amyloid burden (Figure 2, β = 1305, p = 0.006). Conclusion: A PRS for telomere length modestly relates to measured telomere length in older adults and relates to higher amyloid burden. Previous work from our group has highlighted the interaction between measured telomere length and amyloid status such that the association is counter intuitive among those who are biomarker positive. The present results highlight the exciting possibility that telomere length may relate directly to AD biomarkers and open the opportunity for future work further probing the complex interplay between telomere length and AD biomarkers leveraging this powerful genetic tool. [ABSTRACT FROM AUTHOR]
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- 2023
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17. A Genome‐Wide Search for Pleiotropy in More Than 100,000 Harmonized Longitudinal Cognitive Domain Scores.
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Kang, Moonil, Ang, Ting Fang Alvin, Devine, Sherral A., Sherva, Richard, Mukherjee, Shubhabrata, Trittschuh, Emily H., Gibbons, Laura E, Scollard, Phoebe, Lee, Michael L., Choi, Seo‐Eun, Klinedinst, Brandon S, Nakano, Connie, Dumitrescu, Logan C, Hohman, Timothy J., Cuccaro, Michael L., Saykin, Andrew J., Kukull, Walter A., Bennett, David A. A, Wang, Li‐San, and Mayeux, Richard
- Abstract
Background: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD‐related endophenotypes. Method: We conducted genome‐wide scans for cognitive domain performance using harmonized and co‐calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community‐based (FHS, ACT, ROSMAP) and clinic‐based (ADRCs, ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP×age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse‐variance meta‐analysis. Genome‐wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Result: Individual domain and pleiotropy analyses revealed genome‐wide significant (GWS) associations with five established loci for AD and AD‐related disorders (BIN1, CR1, GRN, MS4A6A, APOE) and eight novel loci. ULK2 was associated with executive function in the community‐based cohorts (rs157405, P = 2.19×10−9). GWS associations for language were identified with CDK14 in the clinic‐based cohorts (rs705353, P = 1.73×10−8) and LINC02712 in the total sample (rs145012974, P = 3.66×10−8). GRN (rs5848, P = 4.21×10−8) and PURG (rs117523305, P = 1.73×10−8) were associated with memory in the total and community‐based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12×10−8) in the clinic‐based cohorts, and with NCALD (rs56162098, P = 1.23×10−9) and PTPRD (rs145989094, P = 8.34×10−9) in the community‐based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09×10−8) and PTPRD (rs145989094, P = 3.85×10−8) in the community‐based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion: Our results provide some insight into genes associated with domain‐specific cognitive impairment and AD, as well as a conduit toward a syndrome‐specific precision medicine approach to AD. Increasing the size of datasets by applying the confirmatory factor analysis approach to derive harmonized measures of cognitive performance would likely enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
18. Single‐cell Transcriptomes Reveal Cell‐type Specific Roles of VEGF Family Genes in the Pathogenesis of Alzheimer's Disease.
- Author
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Wu, Yiyang, Dumitrescu, Logan C, De Jager, Philip L, Menon, Vilas, Schneider, Julie A, Bennett, David A. A, Petyuk, Vladislav A, and Hohman, Timothy J.
- Abstract
Background: The role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer's disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. Yet, cell‐specific alterations are not well characterized. To disentangle VEGFs' cell‐specific effect on AD‐related traits, we performed association analyses of mRNA expression from 10 VEGF genes with cognitive performance and AD pathology in eight brain cell types using a large single nucleus RNA sequencing dataset from human brain. Method: This project utilized recently published single‐cell transcriptomes derived from dorsolateral prefrontal cortex tissues of 424 donors collected at Rush Alzheimer's Disease Center. Processed single cell RNA sequencing data were acquired from AD Knowledge Portal (syn2580853). Mean age at death was 89 years, 68% were females, and 37% were AD cases. Negative binomial lognormal mixed models implemented in the NEBULA R package were used to detect differential expression between AD cases and cognitively normal controls, and to analyze the associations with immunohistochemical amyloid and tangles, and finally to assess cross‐sectional and longitudinal global cognitive scores. Correction for multiple comparisons was completed using the false discovery rate procedure (Pfdr<0.05). Result: Prefrontal cortical FLT1 expression was upregulated in AD participants compared to cognitively normal controls in both endothelial (endo) and microglial (micro) cells. Higher micro‐FLT1, endo‐FLT4, and oligodendrocyte (oligo) VEGFB expression was associated with greater β‐amyloid burden in AD samples, whereas higher VEGFB expression in inhibitory neurons was associated with lower β‐amyloid burden. Higher expression of micro‐FLT1 and oligo‐VEGFB associated with worse cognitive trajectories. Higher micro‐ and endo‐ expression of FLT1 associated with lower cognition scores at the last clinic visit before death. Lastly, higher astrocyte‐expressed NRP1 was associated with lower tangle burden. Conclusion: Consistent with our previously reported bulk tissue results, prefrontal cortical expression of FLT1 and FLT4 were associated with global cognition, longitudinal cognitive trajectories, and AD neuropathology, and these associations appear to be limited to endothelial and microglial cells. In contrast, VEGFB expression seems to have opposite effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD physiopathology. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
19. Genetically Regulated Telomere Length Relates to Brain Amyloidosis.
- Author
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Libby, Julia B., Roshani, Rashedeh, Seto, Mabel, Wang, Ting‐Chen, Nudelman, Kelly N. H., Buckley, Rachel F., Saykin, Andrew J., Mormino, Elizabeth C., Sperling, Reisa A., Mayeux, Richard, Dumitrescu, Logan C, and Hohman, Timothy J.
- Abstract
Background: It is well‐established that telomeres shrink over the course of aging and that this process is genetically regulated. Work from our group and others has highlighted the complex interplay between measured leukocyte telomere length and Alzheimer's Disease (AD) biomarkers over the course of AD. We expand on this work to explore whether a polygenic score predicting telomere length relates to PET measures of brain amyloidosis in the preclinical stages of disease. Method: A Polygenic Risk Score (PRS) of telomere length was built from a published GWAS on telomere length from UK Biobank (N = 472,174). We leveraged genetic data from non‐Hispanic White participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1,414) and the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's study (A4; N = 3,002). The relation of the score to measured telomere length was validated using leukocyte telomere length data from ADNI. A linear regression model was used to evaluate whether the PRS relates to a PET measure of brain amyloidosis in a harmonized dataset including ADNI and A4, with a total sample size of 3,940 after restricting to individuals with both genetic data and amyloid measurements. Covariates included age, sex, and diagnostic status. Result: As expected, telomere PRS related to measured telomeres in ADNI when covarying for age, sex, and baseline diagnosis (Figure 1, p = 0.045). Interestingly, we also observed a counter intuitive association between genetically predicted telomere length and amyloidosis whereby longer predicted telomere length was associated with higher amyloid burden (Figure 2, β = 1305, p = 0.006). Conclusion: A PRS for telomere length modestly relates to measured telomere length in older adults and relates to higher amyloid burden. Previous work from our group has highlighted the interaction between measured telomere length and amyloid status such that the association is counter intuitive among those who are biomarker positive. The present results highlight the exciting possibility that telomere length may relate directly to AD biomarkers and open the opportunity for future work further probing the complex interplay between telomere length and AD biomarkers leveraging this powerful genetic tool. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
20. A Genome‐Wide Search for Pleiotropy in More Than 100,000 Harmonized Longitudinal Cognitive Domain Scores.
- Author
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Kang, Moonil, Ang, Ting Fang Alvin, Devine, Sherral A., Sherva, Richard, Mukherjee, Shubhabrata, Trittschuh, Emily H., Gibbons, Laura E, Scollard, Phoebe, Lee, Michael L., Choi, Seo‐Eun, Klinedinst, Brandon S, Nakano, Connie, Dumitrescu, Logan C, Hohman, Timothy J., Cuccaro, Michael L., Saykin, Andrew J., Kukull, Walter A., Bennett, David A. A, Wang, Li‐San, and Mayeux, Richard
- Abstract
Background: More than 75 common variant loci account for only a portion of the heritability for Alzheimer's disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD‐related endophenotypes. Method: We conducted genome‐wide scans for cognitive domain performance using harmonized and co‐calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community‐based (FHS, ACT, ROSMAP) and clinic‐based (ADRCs, ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP×age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP's main effect and interaction with age. Results across datasets were combined using inverse‐variance meta‐analysis. Genome‐wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Result: Individual domain and pleiotropy analyses revealed genome‐wide significant (GWS) associations with five established loci for AD and AD‐related disorders (BIN1, CR1, GRN, MS4A6A, APOE) and eight novel loci. ULK2 was associated with executive function in the community‐based cohorts (rs157405, P = 2.19×10−9). GWS associations for language were identified with CDK14 in the clinic‐based cohorts (rs705353, P = 1.73×10−8) and LINC02712 in the total sample (rs145012974, P = 3.66×10−8). GRN (rs5848, P = 4.21×10−8) and PURG (rs117523305, P = 1.73×10−8) were associated with memory in the total and community‐based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12×10−8) in the clinic‐based cohorts, and with NCALD (rs56162098, P = 1.23×10−9) and PTPRD (rs145989094, P = 8.34×10−9) in the community‐based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09×10−8) and PTPRD (rs145989094, P = 3.85×10−8) in the community‐based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion: Our results provide some insight into genes associated with domain‐specific cognitive impairment and AD, as well as a conduit toward a syndrome‐specific precision medicine approach to AD. Increasing the size of datasets by applying the confirmatory factor analysis approach to derive harmonized measures of cognitive performance would likely enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
21. Single‐cell Transcriptomes Reveal Cell‐type Specific Roles of VEGF Family Genes in the Pathogenesis of Alzheimer's Disease.
- Author
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Wu, Yiyang, Dumitrescu, Logan C, De Jager, Philip L, Menon, Vilas, Schneider, Julie A, Bennett, David A. A, Petyuk, Vladislav A, and Hohman, Timothy J.
- Abstract
Background: The role of the vascular endothelial growth factors (VEGFs) in the pathogenesis of Alzheimer's disease (AD) has been recently described, including notable changes along the VEGFB/FLT1 signaling pathway. Yet, cell‐specific alterations are not well characterized. To disentangle VEGFs' cell‐specific effect on AD‐related traits, we performed association analyses of mRNA expression from 10 VEGF genes with cognitive performance and AD pathology in eight brain cell types using a large single nucleus RNA sequencing dataset from human brain. Method: This project utilized recently published single‐cell transcriptomes derived from dorsolateral prefrontal cortex tissues of 424 donors collected at Rush Alzheimer's Disease Center. Processed single cell RNA sequencing data were acquired from AD Knowledge Portal (syn2580853). Mean age at death was 89 years, 68% were females, and 37% were AD cases. Negative binomial lognormal mixed models implemented in the NEBULA R package were used to detect differential expression between AD cases and cognitively normal controls, and to analyze the associations with immunohistochemical amyloid and tangles, and finally to assess cross‐sectional and longitudinal global cognitive scores. Correction for multiple comparisons was completed using the false discovery rate procedure (Pfdr<0.05). Result: Prefrontal cortical FLT1 expression was upregulated in AD participants compared to cognitively normal controls in both endothelial (endo) and microglial (micro) cells. Higher micro‐FLT1, endo‐FLT4, and oligodendrocyte (oligo) VEGFB expression was associated with greater β‐amyloid burden in AD samples, whereas higher VEGFB expression in inhibitory neurons was associated with lower β‐amyloid burden. Higher expression of micro‐FLT1 and oligo‐VEGFB associated with worse cognitive trajectories. Higher micro‐ and endo‐ expression of FLT1 associated with lower cognition scores at the last clinic visit before death. Lastly, higher astrocyte‐expressed NRP1 was associated with lower tangle burden. Conclusion: Consistent with our previously reported bulk tissue results, prefrontal cortical expression of FLT1 and FLT4 were associated with global cognition, longitudinal cognitive trajectories, and AD neuropathology, and these associations appear to be limited to endothelial and microglial cells. In contrast, VEGFB expression seems to have opposite effects on amyloid burden depending on the cell types, suggesting its more dynamic role in AD physiopathology. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
22. Low-Dose Aspirin for Optimization of Postpartum Vascular Recovery Following Severe Preeclampsia: A Pilot Study
- Author
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Barr, Logan C., Blom, Jessica N., Pudwell, Jessica, and Smith, Graeme N.
- Published
- 2024
- Full Text
- View/download PDF
23. Subventricular zone stem cell niche injury is associated with intestinal perforation in preterm infants and predicts future motor impairment
- Author
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Epstein, Adrian A., Janos, Sara N., Menozzi, Luca, Pegram, Kelly, Jain, Vaibhav, Bisset, Logan C., Davis, Joseph T., Morrison, Samantha, Shailaja, Aswathy, Guo, Yingqiu, Chao, Agnes S., Abdi, Khadar, Rikard, Blaire, Yao, Junjie, Gregory, Simon G., Fisher, Kimberley, Pittman, Rick, Erkanli, Al, Gustafson, Kathryn E., Carrico, Caroline W.T., Malcolm, William F., Inder, Terrie E., Cotten, C. Michael, Burt, Trevor D., Shinohara, Mari L., Maxfield, Charles M., and Benner, Eric J.
- Abstract
Brain injury is highly associated with preterm birth. Complications of prematurity, including spontaneous or necrotizing enterocolitis (NEC)-associated intestinal perforations, are linked to lifelong neurologic impairment, yet the mechanisms are poorly understood. Early diagnosis of preterm brain injuries remains a significant challenge. Here, we identified subventricular zone echogenicity (SVE) on cranial ultrasound in preterm infants following intestinal perforations. The development of SVE was significantly associated with motor impairment at 2 years. SVE was replicated in a neonatal mouse model of intestinal perforation. Examination of the murine echogenic subventricular zone (SVZ) revealed NLRP3-inflammasome assembly in multiciliated FoxJ1+ependymal cells and a loss of the ependymal border in this postnatal stem cell niche. These data suggest a mechanism of preterm brain injury localized to the SVZ that has not been adequately considered. Ultrasound detection of SVE may serve as an early biomarker for neurodevelopmental impairment after inflammatory disease in preterm infants.
- Published
- 2024
- Full Text
- View/download PDF
24. Survival after reoperation for recurrent glioblastoma.
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Woodroffe, Royce W., Zanaty, Mario, Soni, Neetu, Mott, Sarah L., Helland, Logan C., Pasha, Arham, Maley, Joan, Dhungana, Neha, Jones, Karra A., Monga, Varun, and Greenlee, Jeremy D.W.
- Abstract
• The volume of FLAIR signal hyperintensity on MRI was not found to be associated with prognosis. • Volume of contrast enhancement prior to the initial surgery was associated with TTR and OS. • Patients with involvement of critical/ eloquent areas had a poorer prognosis. Determining which patients will benefit from reoperation for recurrent glioblastoma remains difficult and the impact of the volume of FLAIR signal hyperintensity is not well known. The primary purpose of this study is to analyze the impact of preoperative volume of FLAIR hyperintensity on prognosis. 37 patients who underwent a reoperation for recurrent glioblastoma after initial gross total resection followed by standard chemoradiation were retrospectively reviewed. Volumetric analysis of preoperative MR images from the initial and second surgery was performed and correlated with clinical data. Survival probabilities were estimated using the Kaplan-Meier method and Cox regression to assess the effect of risk factors on time to reoperation (TTR), progression-free survival (PFS) after reoperation, and overall survival (OS). The volumes of FLAIR signal hyperintensity prior to the initial surgery and reoperation were not associated with prognosis. TTR and OS were significantly affected by the preoperative enhancement volume at the initial surgery, with increasing volumes yielding poorer prognosis. Patients with tumor in critical/eloquent areas were found to have a worse prognosis. Median TTR was 11 months, median PFS after reoperation was 3 months, and OS in patients undergoing a reoperation was 21 months. The results suggest FLAIR signal change seen in patients with glioblastoma does not influence time to reoperation, progression-free survival, or overall survival. These findings suggest the amount of FLAIR signal change should not greatly influence a surgeon's decision to perform a second surgical resection compare to other factors, and when appropriate, aggressive surgical intervention should be considered. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
25. Updates in infection risk and management in acute leukemia
- Author
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Logan, C., Koura, D., and Taplitz, R.
- Abstract
Patients with hematologic malignancies are at increased risk of infection, with associated morbidity and mortality. Patients with acute myeloid leukemia (AML) have qualitative and quantitative deficits in granulocytes predisposing to bacterial and fungal infections. Acute lymphoblastic leukemia results in qualitative deficits in lymphocytes, resulting in hypogammaglobulinemia and reduced cell-mediated immunity predisposing to certain bacterial and viral as well as fungal infections. Chemotherapeutic regimens often compound these deficits, result in prolonged periods of severe neutropenia, and disrupt mucosal barriers, further elevating infection risk. Despite advances in antimicrobial therapies and prophylaxis, acute leukemia patients with disease- and treatment-related immunosuppression remain at risk for life-threatening infection, including with resistant organisms, antimicrobial-related adverse events, and higher treatment costs. Additionally, our knowledge of infection risk and drug-drug interactions with new immune-targeted cancer therapeutics is evolving. Here, we review 3 areas in which standard practice is evolving as challenges arise and new experience is gained, including antibiotic use in febrile neutropenia, fungal prophylaxis, and use of targeted therapies.
- Published
- 2020
- Full Text
- View/download PDF
26. 126 264 Assigned Chemical Formulas from an Atmospheric Pressure Photoionization 9.4 T Fourier Transform Positive Ion Cyclotron Resonance Mass Spectrum
- Author
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Krajewski, Logan C., Rodgers, Ryan P., and Marshall, Alan G.
- Abstract
Here, we present atmospheric pressure photoionization (APPI) Fourier transform ion cyclotron resonance (FTICR) mass analysis of a volcanic asphalt sample by acquiring data for 20 Da wide mass segments across a 1000 Da range, stitched into a single composite mass spectrum, and compare to a broad-band mass spectrum for the same sample. The segmented spectrum contained 170 000 peaks with magnitude greater than 6σ of the root-mean-square (rms) baseline noise, for which 126 264 unique elemental compositions could be assigned. Approximately two-thirds of those compositions represent monoisotopic (i.e., chemically different) species. That complexity is higher than that for any previously reported mass spectrum and almost 3 times greater than that obtained from the corresponding broad-band spectrum (59 015). For the segmented mass spectrum, the signal-to-noise ratio (S/N) was significantly higher throughout the spectrum, but especially at the lower and upper ends of mass distribution relative to that of the near-Gaussian broad-band mass distribution. Despite this S/N improvement, mass measurement accuracy was noticeably improved only at lower masses. The increased S/N did, however, yield a higher number of peaks and higher dynamic range throughout the entire segmented spectrum relative to the conventional broad-band spectrum. The additional assigned peaks include higher heteroatom species, as well as additional radicals and isotopologues. Segmenting can require a significant investment in data acquisition and analysis time over broad-band spectroscopy (∼1775% in this case) making it best suited for targeted analysis and/or when complete compositional coverage is important. Finally, the present segmented spectrum contains, to our knowledge, more assigned peaks than anyspectrum of any kind (e.g., UV–vis, infrared, microwave, magnetic resonance, etc.).
- Published
- 2024
- Full Text
- View/download PDF
27. Affinity Constants of Bovine Serum Albumin for 5 nm Gold Nanoparticles (AuNPs) with ω-Functionalized Thiol Monolayers Determined by Fluorescence Spectroscopy
- Author
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Hanigan-Diebel, Jennifer L., Costin, Robert J., Myers, Logan C., Vandermeer, Christopher I., Willis, Miles S., Takhar, Kiran, Odinakachukwu, Ogechukwu V., Carroll, Matthias G., Schiffbauer, Jarrod E., and Lohse, Samuel E.
- Abstract
A detailed understanding of the binding of serum proteins to small (dcore<10 nm) nanoparticles (NPs) is essential for the mediation of protein corona formation in next generation nanotherapeutics. While a number of studies have investigated the details of protein adsorption on large functionalized NPs, small NPs (with a particle surface area comparable in size to the protein) have not received extensive study. This study determined the affinity constant (Ka) of BSA when binding to three different functionalized 5 nm gold nanoparticles (AuNPs). AuNPs were synthesized using three ω-functionalized thiols (mercaptoethoxy–ethoxy–ethanol (MEEE), mercaptohexanoic acid (MHA), and mercaptopentyltrimethylammonium chloride (MPTMA)), giving rise to particles with three different surface charges. The binding affinity of bovine serum albumin (BSA) to the different AuNP surfaces was investigated using UV–visible absorbance spectroscopy, dynamic light scattering (DLS), and fluorescence quenching titrations. Fluorescence titrations indicated that the affinity of BSA was actually highest for small AuNPs with a negative surface charge (MHA-AuNPs). Interestingly, the positively charged MPTMA-AuNPs showed the lowest Kafor BSA, indicating that electrostatic interactions are likely not the primary driving force in binding of BSA to these small AuNPs. Kavalues at 25 °C for MHA, MEEE, and MPTMA-AuNPs were 5.2 ± 0.2 × 107, 3.7 ± 0.2 × 107, and 3.3 ± 0.16 × 107M–1in water, respectively. Fluorescence quenching titrations performed in 100 mM NaCl resulted in lower Kavalues for the charged AuNPs, while the Kavalue for the MEEE-AuNPs remained unchanged. Measurement of the hydrodynamic diameter (Dh) by dynamic light scattering (DLS) suggests that adsorption of 1–2 BSA molecules is sufficient to saturate the AuNP surface. DLS and negative-stain TEM images indicate that, despite the lower observed Kavalues, the binding of MPTMA-AuNPs to BSA likely induces significant protein misfolding and may lead to extensive BSA aggregation at specific BSA:AuNP molar ratios.
- Published
- 2024
- Full Text
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28. Modeling the future of shoulder arthroplasty
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Stadecker, Monica, Kolakowski, Logan C., Pandy, Marcus G., and Frankle, Mark A.
- Abstract
In patients with advanced shoulder pathology requiring arthroplasty, the goal is to restore optimal function and provide sustained pain relief. However, the capacity to select the ideal reconstruction of a specific patient’s shoulder and to predict the resulting functional outcome is limited. Computational modeling of the musculoskeletal system has the potential to expand our foundational knowledge of both the native and prosthetic shoulder joint.
- Published
- 2024
- Full Text
- View/download PDF
29. Estimating the Temperature Experienced by Biomass Particles during Fast Pyrolysis Using Microscopic Analysis of Biochars
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Thompson, Logan C., Ciesielski, Peter N., Jarvis, Mark W., Mukarakate, Calvin, Nimlos, Mark R., and Donohoe, Bryon S.
- Abstract
Biomass particles can experience variable thermal conditions during fast pyrolysis due to differences in their size and morphology, and from local temperature variations within a reactor. These differences lead to increased heterogeneity of the chemical products obtained in the pyrolysis vapors and bio-oil. Here we present a simple, high-throughput method to investigate the thermal history experienced by large ensembles of particles during fast pyrolysis by imaging and quantitative image analysis. We present a correlation between the surface luminance (darkness) of the biochar particle and the highest temperature that it experienced during pyrolysis. Next, we apply this correlation to large, heterogeneous ensembles of char particles produced in a laminar entrained flow reactor (LEFR). The results are used to interpret the actual temperature distributions delivered by the reactor over a range of operating conditions.
- Published
- 2024
- Full Text
- View/download PDF
30. Use of Topotactic Phase Transformations To Obtain Solutions of the Crystal Structures of Highly Disordered Materials
- Author
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Lorson, Logan C., Tai, Onkei, and Foxman, Bruce M.
- Abstract
A straightforward procedure is outlined for prediction of the complete three-dimensional coordinate set for a highly disordered phase. For a mother and daughter phase, where one of the pair has an “unsolvable” structure, one needs only to (a) establish the topotaxy using previously published techniques, (b) obtain the topotactic transformation matrix, φ, between the ordered and highly disordered phase, and (c) apply the transpose of φ–1to obtain a trial set of coordinates for refinement using the reflection data set of the highly disordered phase. For the inclusion compound [Fe(η-C5H5)]·3(NH2)2CS (1), which contains highly disordered ferrocene molecules above 160 K (polymorph 1_I), we found a more ordered structure at low temperature. At 135 K (polymorph 1_II), two ferrocene moieties are present in the thiourea channel in an approximately 1:1 ratio. One is nearly orthogonal (87.0°) to the channel axis, while the other is tipped 16.2° from that direction. Using steps (a–c) outlined above, a trial structure may be obtained for 1_I, and refinement leads to R1= 4.25%. The structure of 1_1, containing 12-fold disordered ferrocene molecules, is similar to that found at temperatures below the phase transition, with a greater amount of the orthogonal orientation (55:45 vs 51:48), consistent with, but lower than, amounts found using solid-state NMR techniques. The low temperature polymorph is a trill, with an approximately 3:1:1 ratio of twin components. The exact alignment of the mother phase and the three daughters has been established using the methods of topotactic analysis described previously.
- Published
- 2024
- Full Text
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31. Mechanical control of cell proliferation patterns in growing epithelial monolayers
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Carpenter, Logan C., Pérez-Verdugo, Fernanda, and Banerjee, Shiladitya
- Abstract
Cell proliferation plays a crucial role in regulating tissue homeostasis and development. However, our understanding of how cell proliferation is controlled in densely packed tissues is limited. Here we develop a computational framework to predict the patterns of cell proliferation in growing epithelial tissues, connecting single-cell behaviors and cell-cell interactions to tissue-level growth. Our model incorporates probabilistic rules governing cell growth, division, and elimination, also taking into account their feedback with tissue mechanics. In particular, cell growth is suppressed and apoptosis is enhanced in regions of high cell density. With these rules and model parameters calibrated using experimental data for MDCK epithelial monolayers, we predict how tissue confinement influences cell size and proliferation dynamics and how single-cell physical properties influence the spatiotemporal patterns of tissue growth. In this model, mechanical feedback between tissue confinement and cell growth leads to enhanced cell proliferation at tissue boundaries, whereas cell growth in the bulk is arrested, recapitulating experimental observations in epithelial tissues. By tuning cellular elasticity and contact inhibition of proliferation we can regulate the emergent patterns of cell proliferation, ranging from uniform growth at low contact inhibition to localized growth at higher contact inhibition. We show that the cell size threshold at G1/S transition governs the homeostatic cell density and tissue turnover rate, whereas the mechanical state of the tissue governs the dynamics of tissue growth. In particular, we find that the cellular parameters affecting tissue pressure play a significant role in determining the overall growth rate. Our computational study thus underscores the impact of cell mechanical properties on the spatiotemporal patterns of cell proliferation in growing epithelial tissues.
- Published
- 2024
- Full Text
- View/download PDF
32. Results from the second year of a collaborative effort to forecast influenza seasons in the United States.
- Author
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Biggerstaff, Matthew, Johansson, Michael, Alper, David, Brooks, Logan C., Chakraborty, Prithwish, Farrow, David C., Hyun, Sangwon, Kandula, Sasikiran, McGowan, Craig, Ramakrishnan, Naren, Rosenfeld, Roni, Shaman, Jeffrey, Tibshirani, Rob, Tibshirani, Ryan J., Vespignani, Alessandro, Yang, Wan, Zhang, Qian, and Reed, Carrie
- Abstract
Accurate forecasts could enable more informed public health decisions. Since 2013, CDC has worked with external researchers to improve influenza forecasts by coordinating seasonal challenges for the United States and the 10 Health and Human Service Regions. Forecasted targets for the 2014–15 challenge were the onset week, peak week, and peak intensity of the season and the weekly percent of outpatient visits due to influenza-like illness (ILI) 1–4 weeks in advance. We used a logarithmic scoring rule to score the weekly forecasts, averaged the scores over an evaluation period, and then exponentiated the resulting logarithmic score. Poor forecasts had a score near 0, and perfect forecasts a score of 1. Five teams submitted forecasts from seven different models. At the national level, the team scores for onset week ranged from <0.01 to 0.41, peak week ranged from 0.08 to 0.49, and peak intensity ranged from <0.01 to 0.17. The scores for predictions of ILI 1–4 weeks in advance ranged from 0.02–0.38 and was highest 1 week ahead. Forecast skill varied by HHS region. Forecasts can predict epidemic characteristics that inform public health actions. CDC, state and local health officials, and researchers are working together to improve forecasts. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
33. Linking Natural Oil Seeps from the Gulf of Mexico to Their Origin by Use of Fourier Transform Ion Cyclotron Resonance Mass Spectrometry.
- Author
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Krajewski, Logan C., Lobodin, Vladislav V., Johansen, Caroline, Bartges, Tessa E., Maksimova, Ekaterina V., MacDonald, Ian R., and Marshall, Alan G.
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- 2018
- Full Text
- View/download PDF
34. Use of Topotactic Phase Transformations To Obtain Solutions of the Crystal Structures of Highly Disordered Materials.
- Author
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Lorson, Logan C., Tai, Onkei, and Foxman, Bruce M.
- Published
- 2018
- Full Text
- View/download PDF
35. 126 264 Assigned Chemical Formulas from an Atmospheric Pressure Photoionization 9.4 T Fourier Transform Positive Ion Cyclotron Resonance Mass Spectrum.
- Author
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Krajewski, Logan C., Rodgers, Ryan P., and Marshall, Alan G.
- Published
- 2017
- Full Text
- View/download PDF
36. Characterization of Ketones Formed in the Open System Corrosion Test of Naphthenic Acids by Fourier Transform Ion Cyclotron Resonance Mass Spectrometry
- Author
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Krajewski, Logan C., Robbins, Winston K., Corilo, Yuri E., Bota, Gheorghe, Marshall, Alan G., and Rodgers, Ryan P.
- Abstract
Because the rate of naphthenic acid corrosion does not correlate with the concentration of acids, it has been proposed that a subset of naphthenic acids in petroleum fractions may be more corrosive than others. The primary corrosion products (iron naphthenates) decompose to form ketones at corrosion temperatures (250–400 °C), so characterization of ketones in corrosion fluids could potentially be used to identify the reactive acids that generated the iron naphthenate. Previous work with model acids has reported the development of a method to characterize such ketones by isolation with strong anion exchange separation and detection, with the assistance of ketone targeting derivatization reagent, by Fourier transform ion cyclotron resonance mass spectrometry. Here, we extend that method to characterize the ketones formed in a corrosion test by use of commercially available naphthenic acids (NAP) in a flow-through reactor. The NAP corrosion test yields a single O1ketones/aldehydes distribution close to that predicted from the O2acids distribution before corrosion, with no bias in the carbon number and a slight bias toward lower double bond equivalents in the reactive acids detected. Ketone distributions did not appear to change over the 24 h test. With a fluid residence time of only ∼30 min at reactor temperature, the results suggest that the ketones were formed rapidly beneath an FeS scale.
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- 2019
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37. Characterization of Ketones Formed in the Open System Corrosion Test of Naphthenic Acids by Fourier Transform Ion Cyclotron Resonance Mass Spectrometry.
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Krajewski, Logan C., Robbins, Winston K., Corilo, Yuri E., Bota, Gheorghe, Marshall, Alan G., and Rodgers, Ryan P.
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- 2019
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38. Alternative splicing and ACMG-AMP-2015-based classification of PALB2 genetic variants: an ENIGMA report
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Lopez-Perolio, Irene, Leman, Raphae¨l, Behar, Raquel, Lattimore, Vanessa, Pearson, John F, Castéra, Laurent, Martins, Alexandra, Vaur, Dominique, Goardon, Nicolas, Davy, Grégoire, Garre, Pilar, García-Barberán, Vanesa, Llovet, Patricia, Pérez-Segura, Pedro, Díaz-Rubio, Eduardo, Caldés, Trinidad, Hruska, Kathleen S, Hsuan, Vickie, Wu, Sitao, Pesaran, Tina, Karam, Rachid, Vallon-Christersson, Johan, Borg, Ake, Investigators, kConFab, Valenzuela-Palomo, Alberto, Velasco, Eladio A, Southey, Melissa, Vreeswijk, Maaike P G, Devilee, Peter, Kvist, Anders, Spurdle, Amanda B, Walker, Logan C, Krieger, Sophie, and de la Hoya, Miguel
- Abstract
BackgroundPALB2monoallelic loss-of-functiongerm-line variants confer a breast cancer risk comparable to the average BRCA2pathogenic variant. Recommendations for risk reduction strategies in carriers are similar. Elaborating robust criteria to identify loss-of-functionvariants in PALB2—without incurring overprediction—is thus of paramount clinical relevance. Towards this aim, we have performed a comprehensive characterisation of alternative splicing in PALB2, analysing its relevance for the classification of truncating and splice site variants according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines.MethodsAlternative splicing was characterised in RNAs extracted from blood, breast and fimbriae/ovary-related human specimens (n=112). RNAseq, RT-PCR/CE and CloneSeq experiments were performed by five contributing laboratories. Centralised revision/curation was performed to assure high-quality annotations. Additional splicing analyses were performed in PALB2c.212–1G>A, c.1684+1G>A, c.2748+2T>G, c.3113+5G>A, c.3350+1G>A, c.3350+4A>C and c.3350+5G>A carriers. The impact of the findings on PVS1 status was evaluated for truncating and splice site variant.ResultsWe identified 88 naturally occurring alternative splicing events (81 newly described), including 4 in-frame events predicted relevant to evaluate PVS1 status of splice site variants. We did not identify tissue-specific alternate gene transcripts in breast or ovarian-related samples, supporting the clinical relevance of blood-based splicing studies.ConclusionsPVS1 is not necessarily warranted for splice site variants targeting four PALB2acceptor sites (exons 2, 5, 7 and 10). As a result, rare variants at these splice sites cannot be assumed pathogenic/likely pathogenicwithout further evidences. Our study puts a warning in up to five PALB2genetic variants that are currently reported as pathogenic/likely pathogenicin ClinVar.
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- 2019
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39. Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report
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Spurdle, Amanda B, Greville-Heygate, Stephanie, Antoniou, Antonis C, Brown, Melissa, Burke, Leslie, de la Hoya, Miguel, Domchek, Susan, Do¨rk, Thilo, Firth, Helen V, Monteiro, Alvaro N, Mensenkamp, Arjen, Parsons, Michael T, Radice, Paolo, Robson, Mark, Tischkowitz, Marc, Tudini, Emma, Turnbull, Clare, Vreeswijk, Maaike PG, Walker, Logan C, Tavtigian, Sean, and Eccles, Diana M
- Abstract
The vocabulary currently used to describe genetic variants and their consequences reflects many years of studying and discovering monogenic disease with high penetrance. With the recent rapid expansion of genetic testing brought about by wide availability of high-throughput massively parallel sequencing platforms, accurate variant interpretation has become a major issue. The vocabulary used to describe single genetic variants in silico, in vitro, in vivo and as a contributor to human disease uses terms in common, but the meaning is not necessarily shared across all these contexts. In the setting of cancer genetic tests, the added dimension of using data from genetic sequencing of tumour DNA to direct treatment is an additional source of confusion to those who are not experienced in cancer genetics. The language used to describe variants identified in cancer susceptibility genetic testing typically still reflects an outdated paradigm of Mendelian inheritance with dichotomous outcomes. Cancer is a common disease with complex genetic architecture; an improved lexicon is required to better communicate among scientists, clinicians and patients, the risks and implications of genetic variants detected. This review arises from a recognition of, and discussion about, inconsistencies in vocabulary usage by members of the ENIGMA international multidisciplinary consortium focused on variant classification in breast-ovarian cancer susceptibility genes. It sets out the vocabulary commonly used in genetic variant interpretation and reporting, and suggests a framework for a common vocabulary that may facilitate understanding and clarity in clinical reporting of germline genetic tests for cancer susceptibility.
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- 2019
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40. CD8+T cells modulate autosomal dominant polycystic kidney disease progression
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Kleczko, Emily K., Marsh, Kenneth H., Tyler, Logan C., Furgeson, Seth B., Bullock, Bonnie L., Altmann, Christopher J., Miyazaki, Makoto, Gitomer, Berenice Y., Harris, Peter C., Weiser-Evans, Mary C.M., Chonchol, Michel B., Clambey, Eric T., Nemenoff, Raphael A., and Hopp, Katharina
- Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited nephropathy. To date, therapies alleviating the disease have largely focused on targeting abnormalities in renal epithelial cell signaling. ADPKD has many hallmarks of cancer, where targeting T cells has brought novel therapeutic interventions. However, little is known about the role and therapeutic potential of T cells in ADPKD. Here, we used an orthologous ADPKD model, Pkd1p.R3277C (RC), to begin to define the role of T cells in disease progression. Using flow cytometry, we found progressive increases in renal CD8+and CD4+T cells, correlative with disease severity, but with selective activation of CD8+T cells. By immunofluorescence, T cells specifically localized to cystic lesions and increased levels of T-cell recruiting chemokines (CXCL9/CXCL10) were detected by qPCR/in situhybridization in the kidneys of mice, patients, and ADPKD epithelial cell lines. Importantly, immunodepletion of CD8+T cells from one to three months in C57Bl/6 Pkd1RC/RCmice resulted in worsening of ADPKD pathology, decreased apoptosis, and increased proliferation compared to IgG-control, consistent with a reno-protective role of CD8+T cells. Thus, our studies suggest a functional role for T cells, specifically CD8+T cells, in ADPKD progression. Hence, targeting this pathway using immune-oncology agents may represent a novel therapeutic approach for ADPKD.
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- 2018
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41. The Fast Component of hERG Gating Charge: An Interaction between D411 in the S1 and S4 Residues
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Dou, Ying, Macdonald, Logan C., Wu, Yue, and Fedida, David
- Abstract
Kv11.1 (hERG) is a voltage-gated potassium channel that shows very slow ionic current activation kinetics, and an unusual underlying biphasic gating charge movement with fast and slow components that differ greatly in time course. The structural basis and role of the fast component of gating charge (Qfast) is unclear, and its relationship to the slow activation of hERG channels is not understood. In this study we have used the cut-open oocyte voltage-clamp technique to investigate the relationship of fast gating charge movement-to-residue interactions between D411 at the bottom of the S1, and lower S4 domain charged and uncharged residues. Neutralization of D411 or K538 and V535A prevented Qfastand greatly accelerated overall charge movement. Voltage-clamp fluorometry showed a loss of a fast component of S4 fluorescence in D411N, V535A, and K538Q upon depolarization, whereas [2-(trimethyl ammonium) ethyl] methanethiosulfonate chloride modification of I521C in the outer S4 was enhanced at more negative potentials and at earlier times in these same mutants. A functional interaction between these regions during activation was suggested by ΔΔGovalues >4.2 kJ/mol obtained from double mutant cycle analysis. The data indicate that interactions of S1 residue D411 with lower S4 residues stabilizes early closed states of the channel, and that disruption of these interactions results in both faster rates of activation gating and an elimination of the fast component of gating charge movement and of fluorescence. We propose that the Qfastcharge movement during activation accompanies transitions through early closed states of the hERG activation pathway, and that the weak voltage dependence of these transitions limits the overall activation rate of hERG channels. Disruption of the D411-S4 interactions destabilizes these early closed states, leaving hERG channels able to activate at a rate similar to conventional potassium channels.
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- 2017
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42. Calculated pKa Variations Expose Dynamic Allosteric Communication Networks.
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Lang, Eric J. M., Heyes, Logan C., Jameson, Geoffrey B., and Parker, Emily J.
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- 2016
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43. Characterization of Disinfection By-Products from Chromatographically Isolated NOM through High-Resolution Mass Spectrometry.
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Harris, Bradley D., Brown, Taylor A., McGehee, Jimmie L., Houserova, Dominika, Jackson, Benjamin A., Buchel, Brandon C., Krajewski, Logan C., Whelton, Andrew J., and Stenson, Alexandra C.
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- 2015
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44. Method for Isolation and Detection of Ketones Formed from High-Temperature Naphthenic Acid Corrosion.
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Krajewski, Logan C., Lobodin, Vladislav V., Robbins, Winston K., Peng Jin, Bota, Gheorghe, Marshall, Alan G., and Rodgers, Ryan P.
- Published
- 2017
- Full Text
- View/download PDF
45. Process-Driven Math: An Auditory Method of Mathematics Instruction and Assessment for Students who Are Blind or Have Low Vision
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Gulley, Ann P., Smith, Luke A., Price, Jordan A., Prickett, Logan C., and Ragland, Matthew F.
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- 2017
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46. Method for Isolation and Detection of Ketones Formed from High-Temperature Naphthenic Acid Corrosion
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Krajewski, Logan C., Lobodin, Vladislav V., Robbins, Winston K., Jin, Peng, Bota, Gheorghe, Marshall, Alan G., and Rodgers, Ryan P.
- Abstract
Corrosion control at refineries remains a challenge because the mechanism of naphthenic acid (NAP) corrosion is still not fully understood. The rate of NAP corrosion does not correlate with acidity (as measured by total acid number); therefore, it has been suggested that a subset of NAP in petroleum fractions may be more corrosive than others. Because the primary corrosion product (iron naphthenates) may thermally decompose to ketones at corrosion temperatures (250–400 °C), ketones in corrosion fluids could potentially be used to implicate specific problematic acids in corrosion tests. To that end, we have developed a method for isolating and characterizing ketones in corrosion test solutions. Ketones from tests on palmitic and 4-cyclohexyl pentanoic acids (C16H32O2and C11H20O2) have been successfully isolated with a strong anion exchange solid-phase separation. Gas chromatography/mass spectrometry identifies ketones formed as a result of model acid corrosion. Fourier transform ion cyclotron resonance mass spectrometry further confirms the detection of these ketones and structurally confirms ketones by use of a commercially available reagent that targets ketones and aldehydes. Additional oxygen species generated in the corrosion test likely result from reactions between dissolved atmospheric oxygen and the mineral oil matrix. With this method now validated, it can be applied in future studies of more complex acid mixtures to determine any structural specificity in naphthenic acid corrosion.
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- 2017
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47. Estimating the Temperature Experienced by Biomass Particles during Fast Pyrolysis Using Microscopic Analysis of Biochars.
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Thompson, Logan C., Ciesielski, Peter N., Jarvis, Mark W., Mukarakate, Calvin, Nimlos, Mark R., and Donohoe, Bryon S.
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- 2017
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48. Varenicline Reduces Alcohol Intake During Repeated Cycles of Alcohol Reaccess Following Deprivation in Alcohol‐Preferring (P) Rats
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Froehlich, Janice C., Nicholson, Emily R., Dilley, Julian E., Filosa, Nick J., Rademacher, Logan C., and Smith, Teal N.
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Most alcoholics experience periods of voluntary alcohol abstinence or imposed alcohol deprivation followed by a return to alcohol drinking. This study examined whether varenicline (VAR) reduces alcohol intake during a return to drinking after periods of alcohol deprivation in rats selectively bred for high alcohol drinking (the alcohol preferring or “P” rats). Alcohol‐experienced P rats were given 24‐hour access to food and water and scheduled access to alcohol (15% and 30% v/v) for 2 h/d. After 4 weeks, rats were deprived of alcohol for 2 weeks, followed by reaccess to alcohol for 2 weeks, and this pattern was repeated for a total of 3 cycles. Rats were fed either vehicle (VEH) or VAR, in doses of 0.5, 1.0, or 2.0 mg/kg BW, at 1 hour prior to onset of the daily alcohol reaccess period for the first 5 days of each of the 3 alcohol reaccess cycles. Low‐dose VAR(0.5 mg/kg BW) reduced alcohol intake during the 5 days of drug treatment in alcohol reaccess cycles 1 and 2. Higher doses of VAR(1.0 mg/kg BWand 2.0 mg/kg BW) reduced alcohol intake during the 5 days of treatment in all 3 alcohol reaccess cycles. The decrease in alcohol intake disappeared with termination of VARtreatment in all alcohol reaccess cycles. The results demonstrate that VARdecreases alcohol intake during multiple cycles of alcohol reaccess following alcohol deprivation in rats and suggests that it may prevent a return to heavy alcohol drinking during a lapse from alcohol abstinence in humans with alcohol use disorder. Varenicline was administered (fed) orally during the first 5 days of alcohol reaccess after each of 3 cycles of alcohol deprivation. Varenicline reduced alcohol intake during all 3 cycles of alcohol reaccess. Varenicline may be useful for preventing a return to heavy drinking should alcohol relapse occur during alcohol abstinence.
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- 2017
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49. Thermal Stability of Optically Transparent Alpha-Zirconium Phosphate/Poly(methyl methacrylate) Nanocomposites with High Particle Loading
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Hatanaka, Logan C., Diaz, Agustin, Wang, Qingsheng, Cheng, Zhengdong, and Mannan, M. Sam
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Polymeric nanocomposites have gained attention over the past few decades for their enhanced thermal stability and degradation. However, the reactions involved in a polymer nanocomposite can vary significantly from system to system, making it necessary to investigate novel nanofillers in search for more effective materials. Nanocomposites comprised of alpha-zirconium phosphate (ZrP) nanosheets in poly (methyl methacrylate) (PMMA) were prepared with a wide range of nanoparticle loadings (0, 5, 10, and 30 wt.% ZrP in PMMA). The ZrP nanocomposites were characterized using UV-visible spectroscopy (UV-vis), x-ray diffraction (XRD), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Nanocomposites were well dispersed and optically transparent as shown by XRD and UV-vis. However in the UV region, transparent ZrP nanocomposites possessed excellent UV scattering properties, significantly reducing the transmittance of UV-light, while remaining transparent to the visual spectrum. Thermal stability studies using TGA and DTG showed the peak mass loss rate (PMLR) was reduced by 10% and simultaneously shifted to higher temperatures by 41 °C. Since the nanocomposites in this work cover such a large range of ZrP loadings, large amounts of high-temperature residuals were encountered after TGA studies, indicating that the high loading ZrP nanocomposites are largely noncombustible. In addition, DSC studies showed that ZrP content does affect the glass transition temperature, but not enough to limit the application in which ZrP nanocomposites could be used. These results point to ZrP nanocomposites being useful as polymer replacements, behaving like polymers until the event of a fire, in which case they are largely noncombustible.
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- 2017
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50. Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers
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Walker, Logan C, Marquart, Louise, Pearson, John F, Wiggins, George A R, O'Mara, Tracy A, Parsons, Michael T, Barrowdale, Daniel, McGuffog, Lesley, Dennis, Joe, Benitez, Javier, Slavin, Thomas P, Radice, Paolo, Frost, Debra, Godwin, Andrew K, Meindl, Alfons, Schmutzler, Rita Katharina, Isaacs, Claudine, Peshkin, Beth N, Caldes, Trinidad, Hogervorst, Frans BL, Lazaro, Conxi, Jakubowska, Anna, Montagna, Marco, Chen, Xiaoqing, Offit, Kenneth, Hulick, Peter J, Andrulis, Irene L, Lindblom, Annika, Nussbaum, Robert L, Nathanson, Katherine L, Chenevix-Trench, Georgia, Antoniou, Antonis C, Couch, Fergus J, and Spurdle, Amanda B
- Abstract
Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.
- Published
- 2017
- Full Text
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