88 results on '"Macpherson CR"'
Search Results
2. The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants.
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Mørup SB, Leung P, Reilly C, Sherman BT, Chang W, Milojevic M, Milinkovic A, Liappis A, Borgwardt L, Petoumenos K, Paredes R, Mistry SS, MacPherson CR, Lundgren J, Helleberg M, Reekie J, and Murray DD
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- Humans, Male, Female, Adult, Genotype, Middle Aged, Receptor, Interferon alpha-beta genetics, Cohort Studies, Disease Progression, CD4 Lymphocyte Count, HIV Infections virology, HIV Infections genetics, HIV Infections immunology, HIV-1 genetics, Polymorphism, Single Nucleotide, Viral Load, Interferon Type I genetics
- Abstract
Background: Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL)., Methods: Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025)., Results: The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4
+ T-cell count, CD4+ /CD8+ T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants., Conclusion: Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME., (© 2024. The Author(s).)- Published
- 2024
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3. Predicting type 2 diabetes risk before and after solid organ transplantation using polygenic scores in a Danish cohort.
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Dos Santos Q, Leung P, Thorball CW, Ledergerber B, Fellay J, MacPherson CR, Hornum M, Terrones-Campos C, Rasmussen A, Gustafsson F, Perch M, Sørensen SS, Ekenberg C, Lundgren JD, Feldt-Rasmussen B, and Reekie J
- Abstract
Type 2 diabetes mellitus (T2DM) can be multifactorial where both genetics and environmental factors play a role. We aimed to investigate the use of polygenic risk scores (PRS) in the prediction of pre-transplant T2DM and post-transplant diabetes mellitus (PTDM) among solid organ transplant (SOT) patients. Using non-genetic risk scores alone; and the combination with PRS, separate logistic regression models were built and compared using receiver operator curves. Patients were assessed pre-transplant and in three post-transplant periods: 0-45, 46-365 and >365 days. A higher PRS was significantly associated with increased odds of pre-transplant T2DM. However, no improvement was observed for pre-transplant T2DM prediction when comparing PRS combined with non-genetic risk scores to using non-genetic risk scores alone. This was also true for predictions of PTDM in all three post-transplant periods. This study demonstrated that polygenic risk was only associated with the risk of T2DM among SOT recipients prior to transplant and not for PTDM. Combining PRS with a clinical model of non-genetic risk scores did not significantly improve the predictive ability, indicating its limited clinical utility in identifying patients at high risk for T2DM before transplantation, suggesting that non-genetic or different genetic factors may contribute to PTDM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 dos Santos, Leung, Thorball, Ledergerber, Fellay, MacPherson, Hornum, Terrones-Campos, Rasmussen, Gustafsson, Perch, Sørensen, Ekenberg, Lundgren, Feldt‐Rasmussen and Reekie.)
- Published
- 2023
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4. Associations of functional human leucocyte antigen class I groups with HIV viral load in a heterogeneous cohort.
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Zucco AG, Bennedbæk M, Ekenberg C, Gabrielaite M, Leung P, Polizzotto MN, Kan V, Murray DD, Lundgren JD, and MacPherson CR
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- Humans, Viral Load, Histocompatibility Antigens Class I genetics, HLA-B Antigens genetics, Alleles, HIV Infections drug therapy, HIV Seropositivity, HIV-1 genetics
- Abstract
Objective: Human leucocyte antigen (HLA) class I alleles are the main host genetic factors involved in controlling HIV-1 viral load (VL). Nevertheless, HLA diversity has proven a significant challenge in association studies. We assessed how accounting for binding affinities of HLA class I alleles to HIV-1 peptides facilitate association testing of HLA with HIV-1 VL in a heterogeneous cohort., Design: Cohort from the Strategic Timing of AntiRetroviral Treatment (START) study., Methods: We imputed HLA class I alleles from host genetic data (2546 HIV+ participants) and sampled immunopeptidomes from 2079 host-paired viral genomes (targeted amplicon sequencing). We predicted HLA class I binding affinities to HIV-1 and unspecific peptides, grouping alleles into functional clusters through consensus clustering. These functional HLA class I clusters were used to test associations with HIV VL., Results: We identified four clades totaling 30 HLA alleles accounting for 11.4% variability in VL. We highlight HLA-B∗57:01 and B∗57:03 as functionally similar but yet overrepresented in distinct ethnic groups, showing when combined a protective association with HIV+ VL (log, β -0.25; adj. P-value < 0.05). We further demonstrate only a slight power reduction when using unspecific immunopeptidomes, facilitating the use of the inferred functional HLA groups in other studies., Conclusion: The outlined computational approach provides a robust and efficient way to incorporate HLA function and peptide diversity, aiding clinical association studies in heterogeneous cohorts. To facilitate access to the proposed methods and results we provide an interactive application for exploring data., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2023
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5. Metabolic Profiling Early Post-Allogeneic Haematopoietic Cell Transplantation in the Context of CMV Infection.
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Rasmussen KK, Dos Santos Q, MacPherson CR, Zucco AG, Gjærde LK, Ilett EE, Lodding I, Helleberg M, Lundgren JD, Nielsen SD, Brix S, Sengeløv H, and Murray DD
- Abstract
Immune dysfunction resulting from allogeneic haematopoietic stem cell transplantation (aHSCT) predisposes one to an elevated risk of cytomegalovirus (CMV) infection. Changes in metabolism have been associated with adverse outcomes, and in this study, we explored the associations between metabolic profiles and post-transplantation CMV infection using plasma samples collected 7-33 days after aHSCT. We included 68 aHSCT recipients from Rigshospitalet, Denmark, 50% of whom experienced CMV infection between days 34-100 post-transplantation. First, we investigated whether 12 metabolites selected based on the literature were associated with an increased risk of post-transplantation CMV infection. Second, we conducted an exploratory network-based analysis of the complete metabolic and lipidomic profiles in relation to clinical phenotypes and biological pathways. Lower levels of trimethylamine N-oxide were associated with subsequent CMV infection (multivariable logistic regression: OR = 0.63; 95% CI = [0.41; 0.87]; p = 0.01). Explorative analysis revealed 12 clusters of metabolites or lipids, among which one was predictive of CMV infection, and the others were associated with conditioning regimens, age upon aHSCT, CMV serostatus, and/or sex. Our results provide evidence for an association between the metabolome and CMV infection post-aHSCT that is independent of known risk factors.
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- 2023
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6. Development of a machine learning model for early prediction of plasma leakage in suspected dengue patients.
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Zargari Marandi R, Leung P, Sigera C, Murray DD, Weeratunga P, Fernando D, Rodrigo C, Rajapakse S, and MacPherson CR
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- Humans, Predictive Value of Tests, ROC Curve, Algorithms, Hospitalization, Dengue diagnosis
- Abstract
Background: At least a third of dengue patients develop plasma leakage with increased risk of life-threatening complications. Predicting plasma leakage using laboratory parameters obtained in early infection as means of triaging patients for hospital admission is important for resource-limited settings., Methods: A Sri Lankan cohort including 4,768 instances of clinical data from N = 877 patients (60.3% patients with confirmed dengue infection) recorded in the first 96 hours of fever was considered. After excluding incomplete instances, the dataset was randomly split into a development and a test set with 374 (70%) and 172 (30%) patients, respectively. From the development set, five most informative features were selected using the minimum description length (MDL) algorithm. Random forest and light gradient boosting machine (LightGBM) were used to develop a classification model using the development set based on nested cross validation. An ensemble of the learners via average stacking was used as the final model to predict plasma leakage., Results: Lymphocyte count, haemoglobin, haematocrit, age, and aspartate aminotransferase were the most informative features to predict plasma leakage. The final model achieved the area under the receiver operating characteristics curve, AUC = 0.80 with positive predictive value, PPV = 76.9%, negative predictive value, NPV = 72.5%, specificity = 87.9%, and sensitivity = 54.8% on the test set., Conclusion: The early predictors of plasma leakage identified in this study are similar to those identified in several prior studies that used non-machine learning based methods. However, our observations strengthen the evidence base for these predictors by showing their relevance even when individual data points, missing data and non-linear associations were considered. Testing the model on different populations using these low-cost observations would identify further strengths and limitations of the presented model., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zargari Marandi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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7. Association between ten-eleven methylcytosine dioxygenase 2 genetic variation and viral load in people with HIV.
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Murray DD, Grund B, MacPherson CR, Ekenberg C, Zucco AG, Reekie J, Dominguez-Dominguez L, Leung P, Fusco D, Gras J, Gerstoft J, Helleberg M, Borges ÁH, Polizzotto MN, and Lundgren JD
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- Humans, CD4 Lymphocyte Count, Polymorphism, Single Nucleotide, Viral Load, Dioxygenases genetics, HIV Infections drug therapy, HIV Infections genetics
- Abstract
Introduction: Identifying genetic factors that influence HIV-pathogenesis is critical for understanding disease pathways. Previous studies have suggested a role for the human gene ten-eleven methylcytosine dioxygenase 2 (TET2) in modulating HIV-pathogenesis., Methods: We assessed whether genetic variation in TET2 was associated with markers of HIV-pathogenesis using both gene level and single nucleotide polymorphism (SNP) level association in 8512 HIV-positive persons across five clinical trial cohorts., Results: Variation at both the gene and SNP-level of TET2 was found to be associated with levels of HIV viral load (HIV-VL) consistently in the two cohorts that recruited antiretroviral-naïve participants. The SNPs occurred in two clusters of high linkage disequilibrium (LD), one associated with high HIV-VL and the other low HIV-VL, and were predominantly found in Black participants., Conclusion: Genetic variation in TET2 was associated with HIV-VL in two large antiretroviral therapy (ART)-naive clinical trial cohorts. The role of TET2 in HIV-pathogenesis warrants further investigation., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)
- Published
- 2023
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8. Pre-Transplant Prediction of Acute Graft-versus-Host Disease Using the Gut Microbiome.
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Zargari Marandi R, Jørgensen M, Ilett EE, Nørgaard JC, Noguera-Julian M, Paredes R, Lundgren JD, Sengeløv H, and MacPherson CR
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- Humans, Transplantation, Homologous, Bacteria, Gastrointestinal Microbiome physiology, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Gut microbiota is thought to influence host responses to allogeneic hematopoietic stem cell transplantation (aHSCT). Recent evidence points to this post-transplant for acute graft-versus-host disease (aGvHD). We asked whether any such association might be found pre-transplant and conducted a metagenome-wide association study (MWAS) to explore. Microbial abundance profiles were estimated using ensembles of Kaiju, Kraken2, and DeepMicrobes calls followed by dimensionality reduction. The area under the curve (AUC) was used to evaluate classification of the samples (aGvHD vs. none) using an elastic net to test the relevance of metagenomic data. Clinical data included the underlying disease (leukemia vs. other hematological malignancies), recipient age, and sex. Among 172 aHSCT patients of whom 42 developed aGVHD post transplantation, a total of 181 pre-transplant tool samples were analyzed. The top performing model predicting risk of aGVHD included a reduced species profile (AUC = 0.672). Beta diversity (37% in Jaccard's Nestedness by mean fold change, p < 0.05) was lower in those developing aGvHD. Ten bacterial species including Prevotella and Eggerthella genera were consistently found to associate with aGvHD in indicator species analysis, as well as relief and impurity-based algorithms. The findings support the hypothesis on potential associations between gut microbiota and aGvHD based on a data-driven approach to MWAS. This highlights the need and relevance of routine stool collection for the discovery of novel biomarkers.
- Published
- 2022
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9. Metabolic Potential of the Gut Microbiome Is Significantly Impacted by Conditioning Regimen in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.
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Jørgensen M, Nørgaard JC, Ilett EE, Marandi RZ, Noguera-Julian M, Paredes R, Murray DD, Lundgren J, MacPherson CR, and Sengeløv H
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- Adult, Humans, Immune System pathology, Transplantation Conditioning, Gastrointestinal Microbiome, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation
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Allogeneic hematopoietic stem cell transplantation (aHSCT) is a putative curative treatment for malignant hematologic disorders. During transplantation, the immune system is suppressed/eradicated through a conditioning regimen (non-myeloablative or myeloablative) and replaced with a donor immune system. In our previous study, we showed changes in gut taxonomic profiles and a decrease in bacterial diversity post-transplant. In this study, we expand the cohort with 114 patients and focus on the impact of the conditioning regimens on taxonomic features and the metabolic functions of the gut bacteria. This is, to our knowledge, the first study to examine the metabolic potential of the gut microbiome in this patient group. Adult aHSCT recipients with shotgun sequenced stool samples collected day -30 to +28 relative to aHSCT were included. One sample was selected per patient per period: pre-aHSCT (day -30-0) and post-aHSCT (day 1-28). In total, 254 patients and 365 samples were included. Species richness, alpha diversity, gene richness and metabolic richness were all lower post-aHSCT than pre-aHSCT and the decline was more pronounced for the myeloablative group. The myeloablative group showed a decline in 36 genera and an increase in 15 genera. For the non-myeloablative group, 30 genera decreased and 16 increased with lower fold changes than observed in the myeloablative group. For the myeloablative group, 32 bacterial metabolic functions decreased, and one function increased. For the non-myeloablative group, three functions decreased, and two functions increased. Hence, the changes in taxonomy post-aHSCT caused a profound decline in bacterial metabolic functions especially in the myeloablative group, thus providing new evidence for associations of myeloablative conditioning and gut dysbiosis from a functional perspective .
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- 2022
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10. The gut microbiome in patients with chronic lymphocytic leukemia.
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Faitová T, Svanberg R, Da Cunha-Bang C, Ilett EE, Jørgensen M, Noguera-Julian M, Paredes R, MacPherson CR, and Niemann CU
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- Humans, Gastrointestinal Microbiome, Leukemia, Lymphocytic, Chronic, B-Cell, Skin Neoplasms
- Published
- 2022
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11. Personalized survival probabilities for SARS-CoV-2 positive patients by explainable machine learning.
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Zucco AG, Agius R, Svanberg R, Moestrup KS, Marandi RZ, MacPherson CR, Lundgren J, Ostrowski SR, and Niemann CU
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- Humans, Machine Learning, ROC Curve, Retrospective Studies, Risk Factors, COVID-19, SARS-CoV-2
- Abstract
Interpretable risk assessment of SARS-CoV-2 positive patients can aid clinicians to implement precision medicine. Here we trained a machine learning model to predict mortality within 12 weeks of a first positive SARS-CoV-2 test. By leveraging data on 33,938 confirmed SARS-CoV-2 cases in eastern Denmark, we considered 2723 variables extracted from electronic health records (EHR) including demographics, diagnoses, medications, laboratory test results and vital parameters. A discrete-time framework for survival modelling enabled us to predict personalized survival curves and explain individual risk factors. Performance on the test set was measured with a weighted concordance index of 0.95 and an area under the curve for precision-recall of 0.71. Age, sex, number of medications, previous hospitalizations and lymphocyte counts were identified as top mortality risk factors. Our explainable survival model developed on EHR data also revealed temporal dynamics of the 22 selected risk factors. Upon further validation, this model may allow direct reporting of personalized survival probabilities in routine care., (© 2022. The Author(s).)
- Published
- 2022
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12. The association of human leukocyte antigen alleles with clinical disease progression in HIV-positive cohorts with varied treatment strategies.
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Ekenberg C, Reekie J, Zucco AG, Murray DD, Sharma S, Macpherson CR, Babiker A, Kan V, Lane HC, Neaton JD, and Lundgren JD
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- Alleles, Cohort Studies, Disease Progression, HIV-1, Humans, HIV Infections complications, HIV Infections drug therapy, HIV Infections genetics, HLA Antigens genetics
- Abstract
Objectives: The Strategic Timing of AntiRetroviral Treatment (START) and Strategies for Management of Antiretroviral Therapy (SMART) trials demonstrated that ART can partly reverse clinically defined immune dysfunction induced by HIV replication. As control of HIV replication is influenced by the HLA region, we explored whether HLA alleles independently influence the risk of clinical events in HIV+ individuals., Design: Cohort study., Methods: In START and SMART participants, associations between imputed HLA alleles and AIDS, infection-related cancer, herpes virus-related AIDS events, chronic inflammation-related conditions, and bacterial pneumonia were assessed. Cox regression was used to estimate hazard ratios for the risk of events among allele carriers versus noncarriers. Models were adjusted for sex, age, geography, race, time-updated CD4+ T-cell counts and HIV viral load and stratified by treatment group within trials. HLA class I and II alleles were analyzed separately. The Benjamini--Hochberg procedure was used to limit the false discovery rate to less than 5% (i.e. q value <0.05)., Results: Among 4829 participants, there were 132 AIDS events, 136 chronic inflammation-related conditions, 167 bacterial pneumonias, 45 infection-related cancers, and 49 herpes virus-related AIDS events. Several associations with q value less than 0.05 were found: HLA-DQB1∗06:04 and HLA-DRB1∗13:02 with AIDS (adjusted HR [95% CI] 2.63 [1.5-4.6] and 2.25 [1.4-3.7], respectively), HLA-B∗15:17 and HLA-DPB1∗15:01 with bacterial pneumonia (4.93 [2.3-10.7] and 4.33 [2.0-9.3], respectively), and HLA-A∗69:01 with infection-related cancer (15.26 [3.5-66.7]). The carriage frequencies of these alleles were 10% or less., Conclusion: This hypothesis-generating study suggests that certain HLA alleles may influence the risk of immune dysfunction-related events irrespective of viral load and CD4+ T-cell count., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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13. Machine learning can identify newly diagnosed patients with CLL at high risk of infection.
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Agius R, Brieghel C, Andersen MA, Pearson AT, Ledergerber B, Cozzi-Lepri A, Louzoun Y, Andersen CL, Bergstedt J, von Stemann JH, Jørgensen M, Tang ME, Fontes M, Bahlo J, Herling CD, Hallek M, Lundgren J, MacPherson CR, Larsen J, and Niemann CU
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- Aged, Algorithms, Antineoplastic Agents therapeutic use, Benchmarking, Cohort Studies, Databases, Factual, Female, Humans, Infections etiology, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Male, Middle Aged, Infections diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell complications, Machine Learning, Risk Factors
- Abstract
Infections have become the major cause of morbidity and mortality among patients with chronic lymphocytic leukemia (CLL) due to immune dysfunction and cytotoxic CLL treatment. Yet, predictive models for infection are missing. In this work, we develop the CLL Treatment-Infection Model (CLL-TIM) that identifies patients at risk of infection or CLL treatment within 2 years of diagnosis as validated on both internal and external cohorts. CLL-TIM is an ensemble algorithm composed of 28 machine learning algorithms based on data from 4,149 patients with CLL. The model is capable of dealing with heterogeneous data, including the high rates of missing data to be expected in the real-world setting, with a precision of 72% and a recall of 75%. To address concerns regarding the use of complex machine learning algorithms in the clinic, for each patient with CLL, CLL-TIM provides explainable predictions through uncertainty estimates and personalized risk factors.
- Published
- 2020
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14. Association Between Single-Nucleotide Polymorphisms in HLA Alleles and Human Immunodeficiency Virus Type 1 Viral Load in Demographically Diverse, Antiretroviral Therapy-Naive Participants From the Strategic Timing of AntiRetroviral Treatment Trial.
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Ekenberg C, Tang MH, Zucco AG, Murray DD, MacPherson CR, Hu X, Sherman BT, Losso MH, Wood R, Paredes R, Molina JM, Helleberg M, Jina N, Kityo CM, Florence E, Polizzotto MN, Neaton JD, Lane HC, and Lundgren JD
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- Adult, Alleles, Anti-Retroviral Agents therapeutic use, Female, Genome-Wide Association Study, HIV Infections genetics, HIV Infections immunology, HIV Infections virology, HIV-1 isolation & purification, Histocompatibility Antigens Class I immunology, Host-Pathogen Interactions genetics, Host-Pathogen Interactions immunology, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Time Factors, Viral Load drug effects, Viral Load immunology, Anti-Retroviral Agents pharmacology, HIV Infections drug therapy, HIV-1 immunology, Histocompatibility Antigens Class I genetics, Viral Load genetics
- Abstract
The impact of variation in host genetics on replication of human immunodeficiency virus type 1 (HIV-1) in demographically diverse populations remains uncertain. In the current study, we performed a genome-wide screen for associations of single-nucleotide polymorphisms (SNPs) to viral load (VL) in antiretroviral therapy-naive participants (n = 2440) with varying demographics from the Strategic Timing of AntiRetroviral Treatment (START) trial. Associations were assessed using genotypic data generated by a customized SNP array, imputed HLA alleles, and multiple linear regression. Genome-wide significant associations between SNPs and VL were observed in the major histocompatibility complex class I region (MHC I), with effect sizes ranging between 0.14 and 0.39 log10 VL (copies/mL). Supporting the SNP findings, we identified several HLA alleles significantly associated with VL, extending prior observations that the (MHC I) is a major host determinant of HIV-1 control with shared genetic variants across diverse populations and underscoring the limitations of genome-wide association studies as being merely a screening tool., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2019
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15. Clipped histone H3 is integrated into nucleosomes of DNA replication genes in the human malaria parasite Plasmodium falciparum .
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Herrera-Solorio AM, Vembar SS, MacPherson CR, Lozano-Amado D, Meza GR, Xoconostle-Cazares B, Martins RM, Chen P, Vargas M, Scherf A, and Hernández-Rivas R
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- 5' Untranslated Regions, Amino Acid Sequence, Chromatin Immunoprecipitation, Ectopic Gene Expression, Erythrocytes parasitology, Gene Expression Regulation, Histones chemistry, Histones genetics, Humans, Protease Inhibitors pharmacology, Protein Binding, Protein Interaction Domains and Motifs, Proteolysis drug effects, DNA Replication, Histones metabolism, Malaria, Falciparum parasitology, Nucleosomes metabolism, Plasmodium falciparum physiology
- Abstract
Post-translational modifications of histone H3 N-terminal tails are key epigenetic regulators of virulence gene expression and sexual commitment in the human malaria parasite Plasmodium falciparum Here, we identify proteolytic clipping of the N-terminal tail of nucleosome-associated histone H3 at amino acid position 21 as a new chromatin modification. A cathepsin C-like proteolytic clipping activity is observed in nuclear parasite extracts. Notably, an ectopically expressed version of clipped histone H3, PfH3p-HA, is targeted to the nucleus and integrates into mononucleosomes. Furthermore, chromatin immunoprecipitation and next-generation sequencing analysis identified PfH3p-HA as being highly enriched in the upstream region of six genes that play a key role in DNA replication and repair: In these genes, PfH3p-HA demarcates a specific 1.5 kb chromatin island adjacent to the open reading frame. Our results indicate that, in P. falciparum , the process of histone clipping may precede chromatin integration hinting at preferential targeting of pre-assembled PfH3p-containing nucleosomes to specific genomic regions. The discovery of a protease-directed mode of chromatin organization in P. falciparum opens up new avenues to develop new anti-malarials., (© 2019 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2019
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16. Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus.
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Clave E, Araujo IL, Alanio C, Patin E, Bergstedt J, Urrutia A, Lopez-Lastra S, Li Y, Charbit B, MacPherson CR, Hasan M, Melo-Lima BL, Douay C, Saut N, Germain M, Trégouët DA, Morange PE, Fontes M, Duffy D, Di Santo JP, Quintana-Murci L, Albert ML, and Toubert A
- Subjects
- Adult, Aged, Animals, Biomarkers metabolism, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Mice, SCID, Middle Aged, Phenotype, T-Lymphocytes metabolism, Young Adult, Genetic Loci, Genetic Variation, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, gamma-delta genetics, Thymus Gland growth & development
- Abstract
The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
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17. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges.
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Piasecka B, Duffy D, Urrutia A, Quach H, Patin E, Posseme C, Bergstedt J, Charbit B, Rouilly V, MacPherson CR, Hasan M, Albaud B, Gentien D, Fellay J, Albert ML, and Quintana-Murci L
- Subjects
- Adult, Aged, Bacteria immunology, Cohort Studies, Enterotoxins immunology, Female, Fungi immunology, Genotype, Humans, Influenza A virus immunology, Male, Middle Aged, Quantitative Trait Loci, Young Adult, Aging, Gene Expression Regulation immunology, Genetic Variation
- Abstract
The contribution of host genetic and nongenetic factors to immunological differences in humans remains largely undefined. Here, we generated bacterial-, fungal-, and viral-induced immune transcriptional profiles in an age- and sex-balanced cohort of 1,000 healthy individuals and searched for the determinants of immune response variation. We found that age and sex affected the transcriptional response of most immune-related genes, with age effects being more stimulus-specific relative to sex effects, which were largely shared across conditions. Although specific cell populations mediated the effects of age and sex on gene expression, including CD8
+ T cells for age and CD4+ T cells and monocytes for sex, we detected a direct effect of these intrinsic factors for the majority of immune genes. The mapping of expression quantitative trait loci (eQTLs) revealed that genetic factors had a stronger effect on immune gene regulation than age and sex, yet they affected a smaller number of genes. Importantly, we identified numerous genetic variants that manifested their regulatory effects exclusively on immune stimulation, including a Candida albicans -specific master regulator at the CR1 locus. These response eQTLs were enriched in disease-associated variants, particularly for autoimmune and inflammatory disorders, indicating that differences in disease risk may result from regulatory variants exerting their effects only in the presence of immune stress. Together, this study quantifies the respective effects of age, sex, genetics, and cellular heterogeneity on the interindividual variability of immune responses and constitutes a valuable resource for further exploration in the context of different infection risks or disease outcomes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)- Published
- 2018
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18. Identification of the centromeres of Leishmania major : revealing the hidden pieces.
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Garcia-Silva MR, Sollelis L, MacPherson CR, Stanojcic S, Kuk N, Crobu L, Bringaud F, Bastien P, Pagès M, Scherf A, and Sterkers Y
- Subjects
- Amino Acid Sequence, Aneuploidy, Base Sequence, Centromere ultrastructure, Chromatin Immunoprecipitation, Chromosome Mapping, Gene Expression, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, High-Throughput Nucleotide Sequencing, Kinetochores ultrastructure, Leishmania major metabolism, Mitosis, Mosaicism, Protozoan Proteins metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Centromere metabolism, Chromosomes chemistry, Genome, Protozoan, Kinetochores metabolism, Leishmania major genetics, Protozoan Proteins genetics
- Abstract
Leishmania affects millions of people worldwide. Its genome undergoes constitutive mosaic aneuploidy, a type of genomic plasticity that may serve as an adaptive strategy to survive distinct host environments. We previously found high rates of asymmetric chromosome allotments during mitosis that lead to the generation of such ploidy. However, the underlying molecular events remain elusive. Centromeres and kinetochores most likely play a key role in this process, yet their identification has failed using classical methods. Our analysis of the unconventional kinetochore complex recently discovered in Trypanosoma brucei (KKTs) leads to the identification of a Leishmania KKT gene candidate (LmKKT1). The GFP-tagged LmKKT1 displays "kinetochore-like" dynamics of intranuclear localization throughout the cell cycle. By ChIP-Seq assay, one major peak per chromosome is revealed, covering a region of 4 ±2 kb. We find two largely conserved motifs mapping to 14 of 36 chromosomes while a higher density of retroposons are observed in 27 of 36 centromeres. The identification of centromeres and of a kinetochore component of Leishmania chromosomes opens avenues to explore their role in mosaic aneuploidy., (© 2017 The Authors.)
- Published
- 2017
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19. An ApiAP2 member regulates expression of clonally variant genes of the human malaria parasite Plasmodium falciparum.
- Author
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Martins RM, Macpherson CR, Claes A, Scheidig-Benatar C, Sakamoto H, Yam XY, Preiser P, Goel S, Wahlgren M, Sismeiro O, Coppée JY, and Scherf A
- Subjects
- Genes, Protozoan, Genetic Variation, Plasmodium falciparum metabolism, Protozoan Proteins genetics, Protozoan Proteins metabolism, Gene Expression Regulation, Plasmodium falciparum genetics, Protozoan Proteins physiology
- Abstract
Variegated surface antigen expression is key to chronic infection and pathogenesis of the human malaria parasite Plasmodium falciparum. This protozoan parasite expresses distinct surface molecules that are encoded by clonally variant gene families such as var, rif and stevor. The molecular mechanisms governing activation of individual members remain ill-defined. To investigate the molecular events of the initial transcriptional activation process we focused on a member of the apicomplexan ApiAP2 transcription factor family predicted to bind to the 5' upstream regions of the var gene family, AP2-exp (PF3D7_1466400). Viable AP2-exp mutant parasites rely on expressing no less than a short truncated protein including the N-terminal AP2 DNA-binding domain. RNA-seq analysis in mutant parasites revealed transcriptional changes in a subset of exported proteins encoded by clonally variant gene families. Upregulation of RIFINs and STEVORs was validated at the protein levels. In addition, morphological alterations were observed on the surface of the host cells infected by the mutants. This work points to a complex regulatory network of clonally variant gene families in which transcription of a subset of members is regulated by the same transcription factor. In addition, we highlight the importance of the non-DNA binding AP2 domain in functional gene regulation.
- Published
- 2017
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20. Nutrient sensing modulates malaria parasite virulence.
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Mancio-Silva L, Slavic K, Grilo Ruivo MT, Grosso AR, Modrzynska KK, Vera IM, Sales-Dias J, Gomes AR, MacPherson CR, Crozet P, Adamo M, Baena-Gonzalez E, Tewari R, Llinás M, Billker O, and Mota MM
- Subjects
- Animals, Caloric Restriction, Energy Metabolism drug effects, Energy Metabolism genetics, Genetic Complementation Test, Glucose metabolism, Glucose pharmacology, Male, Mice, Mice, Inbred C57BL, Parasitemia blood, Parasitemia genetics, Parasitemia metabolism, Parasitemia parasitology, Parasites genetics, Parasites growth & development, Phosphotransferases deficiency, Phosphotransferases genetics, Plasmodium genetics, Plasmodium growth & development, Rats, Transcriptome drug effects, Virulence drug effects, Gene Expression Regulation drug effects, Malaria parasitology, Parasites metabolism, Parasites pathogenicity, Phosphotransferases metabolism, Plasmodium metabolism, Plasmodium pathogenicity
- Abstract
The lifestyle of intracellular pathogens, such as malaria parasites, is intimately connected to that of their host, primarily for nutrient supply. Nutrients act not only as primary sources of energy but also as regulators of gene expression, metabolism and growth, through various signalling networks that enable cells to sense and adapt to varying environmental conditions. Canonical nutrient-sensing pathways are presumed to be absent from the causative agent of malaria, Plasmodium, thus raising the question of whether these parasites can sense and cope with fluctuations in host nutrient levels. Here we show that Plasmodium blood-stage parasites actively respond to host dietary calorie alterations through rearrangement of their transcriptome accompanied by substantial adjustment of their multiplication rate. A kinome analysis combined with chemical and genetic approaches identified KIN as a critical regulator that mediates sensing of nutrients and controls a transcriptional response to the host nutritional status. KIN shares homology with SNF1/AMPKα, and yeast complementation studies suggest that it is part of a functionally conserved cellular energy-sensing pathway. Overall, these findings reveal a key parasite nutrient-sensing mechanism that is critical for modulating parasite replication and virulence.
- Published
- 2017
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21. First efficient CRISPR-Cas9-mediated genome editing in Leishmania parasites.
- Author
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Sollelis L, Ghorbal M, MacPherson CR, Martins RM, Kuk N, Crobu L, Bastien P, Scherf A, Lopez-Rubio JJ, and Sterkers Y
- Subjects
- Gene Deletion, Recombination, Genetic, CRISPR-Cas Systems, Gene Targeting methods, Genome, Protozoan, Leishmania genetics, Molecular Biology methods, Parasitology methods
- Abstract
Protozoan pathogens that cause leishmaniasis in humans are relatively refractory to genetic manipulation. In this work, we implemented the CRISPR-Cas9 system in Leishmania parasites and demonstrated its efficient use for genome editing. The Cas9 endonuclease was expressed under the control of the Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) promoter and the single guide RNA was produced under the control of the U6snRNA promoter and terminator. As a proof of concept, we chose to knockout a tandemly repeated gene family, the paraflagellar rod-2 locus. We were able to obtain null mutants in a single round of transfection. In addition, we confirmed the absence of off-target editions by whole genome sequencing of two independent clones. Our work demonstrates that CRISPR-Cas9-mediated gene knockout represents a major improvement in comparison with existing methods. Beyond gene knockout, this genome editing tool opens avenues for a multitude of functional studies to speed up research on leishmaniasis., (© 2015 John Wiley & Sons Ltd.)
- Published
- 2015
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22. The PfAlba1 RNA-binding protein is an important regulator of translational timing in Plasmodium falciparum blood stages.
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Vembar SS, Macpherson CR, Sismeiro O, Coppée JY, and Scherf A
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- Animals, Erythrocytes metabolism, Erythrocytes parasitology, Gene Expression Regulation, High-Throughput Nucleotide Sequencing, Host-Parasite Interactions genetics, Humans, Malaria, Falciparum parasitology, Plasmodium falciparum growth & development, Plasmodium falciparum pathogenicity, RNA, Messenger genetics, Trophozoites metabolism, Trophozoites parasitology, Malaria, Falciparum genetics, Plasmodium falciparum genetics, Protein Biosynthesis, Protozoan Proteins genetics, RNA-Binding Proteins genetics
- Abstract
Background: Transcriptome-wide ribosome occupancy studies have suggested that during the intra-erythrocytic lifecycle of Plasmodium falciparum, select mRNAs are post-transcriptionally regulated. A subset of these encodes parasite virulence factors required for invading host erythrocytes, and are currently being developed as vaccine candidates. However, the molecular mechanisms that govern post-transcriptional regulation are currently unknown., Results: We explore the previously identified DNA/RNA-binding protein PfAlba1, which localizes to multiple foci in the cytoplasm of P. falciparum trophozoites. We establish that PfAlba1 is essential for asexual proliferation, and subsequently investigate parasites overexpressing epitope-tagged PfAlba1 to identify its RNA targets and effects on mRNA homeostasis and translational regulation. Using deep sequencing of affinity-purified PfAlba1-associated RNAs, we identify 1193 transcripts that directly bind to PfAlba1 in trophozoites. For 105 such transcripts, 43 % of which are uncharacterized and 13 % of which encode erythrocyte invasion components, the steady state levels significantly change at this stage, evidencing a role for PfAlba1 in maintaining mRNA homeostasis. Additionally, we discover that binding of PfAlba1 to four erythrocyte invasion mRNAs, Rap1, RhopH3, CDPK1, and AMA1, is linked to translation repression in trophozoites whereas release of these mRNAs from a PfAlba1 complex in mature stages correlates with protein synthesis., Conclusions: We show that PfAlba1 binds to a sub-population of asexual stage mRNAs and fine-tunes the timing of translation. This mode of post-transcriptional regulation may be especially important for P. falciparum erythrocyte invasion components that have to be assembled into apical secretory organelles in a highly time-dependent manner towards the end of the parasite's asexual lifecycle.
- Published
- 2015
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23. Flexible guide-RNA design for CRISPR applications using Protospacer Workbench.
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MacPherson CR and Scherf A
- Subjects
- Computational Biology, Databases, Genetic, High-Throughput Nucleotide Sequencing, Humans, Biotechnology methods, CRISPR-Cas Systems, RNA, Guide, CRISPR-Cas Systems, Sequence Analysis, DNA, Software
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- 2015
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24. Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system.
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Ghorbal M, Gorman M, Macpherson CR, Martins RM, Scherf A, and Lopez-Rubio JJ
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- Animals, Clustered Regularly Interspaced Short Palindromic Repeats genetics, Genome, Protozoan, Plasmodium falciparum genetics
- Abstract
Genome manipulation in the malaria parasite Plasmodium falciparum remains largely intractable and improved genomic tools are needed to further understand pathogenesis and drug resistance. We demonstrated the CRISPR-Cas9 system for use in P. falciparum by disrupting chromosomal loci and generating marker-free, single-nucleotide substitutions with high efficiency. Additionally, an artemisinin-resistant strain was generated by introducing a previously implicated polymorphism, thus illustrating the value of efficient genome editing in malaria research.
- Published
- 2014
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25. Identification of estrogen responsive genes using esophageal squamous cell carcinoma (ESCC) as a model.
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Essack M, MacPherson CR, Schmeier S, and Bajic VB
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- Binding Sites, Carcinoma, Squamous Cell metabolism, Esophageal Neoplasms metabolism, Humans, Protein Transport drug effects, Response Elements genetics, Transcription Factors metabolism, Transcription, Genetic drug effects, Carcinoma, Squamous Cell genetics, Esophageal Neoplasms genetics, Estrogens pharmacology, Gene Expression Regulation, Neoplastic drug effects, Gene Expression Regulation, Neoplastic genetics, Systems Biology methods
- Abstract
Background: Estrogen therapy has positively impact the treatment of several cancers, such as prostate, lung and breast cancers. Moreover, several groups have reported the importance of estrogen induced gene regulation in esophageal cancer (EC). This suggests that there could be a potential for estrogen therapy for EC. The efficient design of estrogen therapies requires as complete as possible list of genes responsive to estrogen. Our study develops a systems biology methodology using esophageal squamous cell carcinoma (ESCC) as a model to identify estrogen responsive genes. These genes, on the other hand, could be affected by estrogen therapy in ESCC., Results: Based on different sources of information we identified 418 genes implicated in ESCC. Putative estrogen responsive elements (EREs) mapped to the promoter region of the ESCC genes were used to initially identify candidate estrogen responsive genes. EREs mapped to the promoter sequence of 30.62% (128/418) of ESCC genes of which 43.75% (56/128) are known to be estrogen responsive, while 56.25% (72/128) are new candidate estrogen responsive genes. EREs did not map to 290 ESCC genes. Of these 290 genes, 50.34% (146/290) are known to be estrogen responsive. By analyzing transcription factor binding sites (TFBSs) in the promoters of the 202 (56+146) known estrogen responsive ESCC genes under study, we found that their regulatory potential may be characterized by 44 significantly over-represented co-localized TFBSs (cTFBSs). We were able to map these cTFBSs to promoters of 32 of the 72 new candidate estrogen responsive ESCC genes, thereby increasing confidence that these 32 ESCC genes are responsive to estrogen since their promoters contain both: a/mapped EREs, and b/at least four cTFBSs characteristic of ESCC genes that are responsive to estrogen. Recent publications confirm that 47% (15/32) of these 32 predicted genes are indeed responsive to estrogen., Conclusion: To the best of our knowledge our study is the first to use a cancer disease model as the framework to identify hormone responsive genes. Although we used ESCC as the disease model and estrogen as the hormone, the methodology can be extended analogously to other diseases as the model and other hormones. We believe that our results provide useful information for those interested in genes responsive to hormones and in the design of hormone-based therapies.
- Published
- 2012
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26. The response and recovery of the Arabidopsis thaliana transcriptome to phosphate starvation.
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Woo J, MacPherson CR, Liu J, Wang H, Kiba T, Hannah MA, Wang XJ, Bajic VB, and Chua NH
- Subjects
- Abscisic Acid pharmacology, Arabidopsis drug effects, Cold Temperature, Gene Expression Profiling, Genes, Plant genetics, Genetic Loci genetics, Oligonucleotide Array Sequence Analysis, Organ Specificity drug effects, Organ Specificity genetics, Osmotic Pressure drug effects, Plant Roots drug effects, Plant Roots genetics, Plant Shoots drug effects, Plant Shoots genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, Signal Transduction genetics, Sodium Chloride pharmacology, Transcriptome drug effects, Arabidopsis genetics, Gene Expression Regulation, Plant drug effects, Phosphates deficiency, Transcriptome genetics
- Abstract
Background: Over application of phosphate fertilizers in modern agriculture contaminates waterways and disrupts natural ecosystems. Nevertheless, this is a common practice among farmers, especially in developing countries as abundant fertilizers are believed to boost crop yields. The study of plant phosphate metabolism and its underlying genetic pathways is key to discovering methods of efficient fertilizer usage. The work presented here describes a genome-wide resource on the molecular dynamics underpinning the response and recovery in roots and shoots of Arabidopsis thaliana to phosphate-starvation., Results: Genome-wide profiling by micro- and tiling-arrays (accessible from GEO: GSE34004) revealed minimal overlap between root and shoot transcriptomes suggesting two independent phosphate-starvation regulons. Novel gene expression patterns were detected for over 1000 candidates and were classified as either initial, persistent, or latent responders. Comparative analysis to AtGenExpress identified cohorts of genes co-regulated across multiple stimuli. The hormone ABA displayed a dominant role in regulating many phosphate-responsive candidates. Analysis of co-regulation enabled the determination of specific versus generic members of closely related gene families with respect to phosphate-starvation. Thus, among others, we showed that PHR1-regulated members of closely related phosphate-responsive families (PHT1;1, PHT1;7-9, SPX1-3, and PHO1;H1) display greater specificity to phosphate-starvation than their more generic counterparts., Conclusion: Our results uncover much larger, staged responses to phosphate-starvation than previously described. To our knowledge, this work describes the most complete genome-wide data on plant nutrient stress to-date.
- Published
- 2012
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27. In Silico discovery of transcription factors as potential diagnostic biomarkers of ovarian cancer.
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Kaur M, MacPherson CR, Schmeier S, Narasimhan K, Choolani M, and Bajic VB
- Subjects
- Binding Sites genetics, Computational Biology methods, Female, Gene Expression Regulation, Neoplastic physiology, Humans, Promoter Regions, Genetic genetics, Biomarkers, Tumor metabolism, Estrogens pharmacology, Gene Expression Regulation, Neoplastic drug effects, Genes, Neoplasm genetics, Ovarian Neoplasms diagnosis, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
Background: Our study focuses on identifying potential biomarkers for diagnosis and early detection of ovarian cancer (OC) through the study of transcription regulation of genes affected by estrogen hormone., Results: The results are based on a set of 323 experimentally validated OC-associated genes compiled from several databases, and their subset controlled by estrogen. For these two gene sets we computationally determined transcription factors (TFs) that putatively regulate transcription initiation. We ranked these TFs based on the number of genes they are likely to control. In this way, we selected 17 top-ranked TFs as potential key regulators and thus possible biomarkers for a set of 323 OC-associated genes. For 77 estrogen controlled genes from this set we identified three unique TFs as potential biomarkers., Conclusions: We introduced a new methodology to identify potential diagnostic biomarkers for OC. This report is the first bioinformatics study that explores multiple transcriptional regulators of OC-associated genes as potential diagnostic biomarkers in connection with estrogen responsiveness. We show that 64% of TF biomarkers identified in our study are validated based on real-time data from microarray expression studies. As an illustration, our method could identify CP2 that in combination with CA125 has been reported to be sensitive in diagnosing ovarian tumors.
- Published
- 2011
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28. dPORE-miRNA: polymorphic regulation of microRNA genes.
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Schmeier S, Schaefer U, MacPherson CR, and Bajic VB
- Subjects
- Animals, Base Sequence, Data Collection, Humans, MicroRNAs metabolism, MicroRNAs physiology, Molecular Sequence Data, Polymorphism, Single Nucleotide physiology, Promoter Regions, Genetic, Rats, Software, User-Computer Interface, Databases, Genetic, Gene Expression Regulation genetics, MicroRNAs genetics, Polymorphism, Genetic physiology
- Abstract
Background: MicroRNAs (miRNAs) are short non-coding RNA molecules that act as post-transcriptional regulators and affect the regulation of protein-coding genes. Mostly transcribed by PolII, miRNA genes are regulated at the transcriptional level similarly to protein-coding genes. In this study we focus on human miRNAs. These miRNAs are involved in a variety of pathways and can affect many diseases. Our interest is on possible deregulation of the transcription initiation of the miRNA encoding genes, which is facilitated by variations in the genomic sequence of transcriptional control regions (promoters)., Methodology: Our aim is to provide an online resource to facilitate the investigation of the potential effects of single nucleotide polymorphisms (SNPs) on miRNA gene regulation. We analyzed SNPs overlapped with predicted transcription factor binding sites (TFBSs) in promoters of miRNA genes. We also accounted for the creation of novel TFBSs due to polymorphisms not present in the reference genome. The resulting changes in the original TFBSs and potential creation of new TFBSs were incorporated into the Dragon Database of Polymorphic Regulation of miRNA genes (dPORE-miRNA)., Conclusions: The dPORE-miRNA database enables researchers to explore potential effects of SNPs on the regulation of miRNAs. dPORE-miRNA can be interrogated with regards to: a/miRNAs (their targets, or involvement in diseases, or biological pathways), b/SNPs, or c/transcription factors. dPORE-miRNA can be accessed at http://cbrc.kaust.edu.sa/dpore and http://apps.sanbi.ac.za/dpore/. Its use is free for academic and non-profit users.
- Published
- 2011
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29. An atlas of combinatorial transcriptional regulation in mouse and man.
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Ravasi T, Suzuki H, Cannistraci CV, Katayama S, Bajic VB, Tan K, Akalin A, Schmeier S, Kanamori-Katayama M, Bertin N, Carninci P, Daub CO, Forrest AR, Gough J, Grimmond S, Han JH, Hashimoto T, Hide W, Hofmann O, Kamburov A, Kaur M, Kawaji H, Kubosaki A, Lassmann T, van Nimwegen E, MacPherson CR, Ogawa C, Radovanovic A, Schwartz A, Teasdale RD, Tegnér J, Lenhard B, Teichmann SA, Arakawa T, Ninomiya N, Murakami K, Tagami M, Fukuda S, Imamura K, Kai C, Ishihara R, Kitazume Y, Kawai J, Hume DA, Ideker T, and Hayashizaki Y
- Subjects
- Animals, Cell Differentiation, Evolution, Molecular, Humans, Mice, Monocytes cytology, Organ Specificity, Smad3 Protein metabolism, Trans-Activators metabolism, Gene Expression Regulation, Gene Regulatory Networks, Transcription Factors metabolism
- Abstract
Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution., ((c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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30. Deciphering the transcriptional circuitry of microRNA genes expressed during human monocytic differentiation.
- Author
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Schmeier S, MacPherson CR, Essack M, Kaur M, Schaefer U, Suzuki H, Hayashizaki Y, and Bajic VB
- Subjects
- Binding Sites, Gene Expression Regulation, Humans, MicroRNAs immunology, Monocytes immunology, Promoter Regions, Genetic, Transcription Factors immunology, Cell Differentiation, MicroRNAs genetics, Monocytes cytology, Transcription Factors genetics, Transcription, Genetic
- Abstract
Background: Macrophages are immune cells involved in various biological processes including host defence, homeostasis, differentiation, and organogenesis. Disruption of macrophage biology has been linked to increased pathogen infection, inflammation and malignant diseases. Differential gene expression observed in monocytic differentiation is primarily regulated by interacting transcription factors (TFs). Current research suggests that microRNAs (miRNAs) degrade and repress translation of mRNA, but also may target genes involved in differentiation. We focus on getting insights into the transcriptional circuitry regulating miRNA genes expressed during monocytic differentiation., Results: We computationally analysed the transcriptional circuitry of miRNA genes during monocytic differentiation using in vitro time-course expression data for TFs and miRNAs. A set of TF-->miRNA associations was derived from predicted TF binding sites in promoter regions of miRNA genes. Time-lagged expression correlation analysis was utilised to evaluate the TF-->miRNA associations. Our analysis identified 12 TFs that potentially play a central role in regulating miRNAs throughout the differentiation process. Six of these 12 TFs (ATF2, E2F3, HOXA4, NFE2L1, SP3, and YY1) have not previously been described to be important for monocytic differentiation. The remaining six TFs are CEBPB, CREB1, ELK1, NFE2L2, RUNX1, and USF2. For several miRNAs (miR-21, miR-155, miR-424, and miR-17-92), we show how their inferred transcriptional regulation impacts monocytic differentiation., Conclusions: The study demonstrates that miRNAs and their transcriptional regulatory control are integral molecular mechanisms during differentiation. Furthermore, it is the first study to decipher on a large-scale, how miRNAs are controlled by TFs during human monocytic differentiation. Subsequently, we have identified 12 candidate key controllers of miRNAs during this differentiation process.
- Published
- 2009
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31. Genomic anatomy of the hippocampus.
- Author
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Thompson CL, Pathak SD, Jeromin A, Ng LL, MacPherson CR, Mortrud MT, Cusick A, Riley ZL, Sunkin SM, Bernard A, Puchalski RB, Gage FH, Jones AR, Bajic VB, Hawrylycz MJ, and Lein ES
- Subjects
- Animals, Animals, Newborn, Cholera Toxin metabolism, Imaging, Three-Dimensional, In Situ Hybridization methods, Male, Mice, Mice, Inbred C57BL, Models, Biological, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Neural Cell Adhesion Molecules genetics, Neural Cell Adhesion Molecules metabolism, Neural Pathways anatomy & histology, Neural Pathways metabolism, Principal Component Analysis, Septum Pellucidum anatomy & histology, Septum Pellucidum metabolism, Temporal Lobe anatomy & histology, Temporal Lobe metabolism, Brain Mapping, Gene Expression Regulation, Developmental physiology, Genomics, Hippocampus anatomy & histology, Hippocampus physiology
- Abstract
Availability of genome-scale in situ hybridization data allows systematic analysis of genetic neuroanatomical architecture. Within the hippocampus, electrophysiology and lesion and imaging studies demonstrate functional heterogeneity along the septotemporal axis, although precise underlying circuitry and molecular substrates remain uncharacterized. Application of unbiased statistical component analyses to genome-scale hippocampal gene expression data revealed robust septotemporal molecular heterogeneity, leading to the identification of a large cohort of genes with robust regionalized hippocampal expression. Manual mapping of heterogeneous CA3 pyramidal neuron expression patterns demonstrates an unexpectedly complex molecular parcellation into a relatively coherent set of nine expression domains in the septal/temporal and proximal/distal axes with reciprocal, nonoverlapping boundaries. Unique combinatorial profiles of adhesion molecules within these domains suggest corresponding differential connectivity, which is demonstrated for CA3 projections to the lateral septum using retrograde labeling. This complex, discrete molecular architecture provides a novel paradigm for predicting functional differentiation across the full septotemporal extent of the hippocampus.
- Published
- 2008
- Full Text
- View/download PDF
32. Prioritizing genes of potential relevance to diseases affected by sex hormones: an example of myasthenia gravis.
- Author
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Kaur M, Schmeier S, MacPherson CR, Hofmann O, Hide WA, Taylor S, Willcox N, and Bajic VB
- Subjects
- Estrogens metabolism, Gene Expression Regulation, Humans, Thymus Gland metabolism, Gonadal Steroid Hormones metabolism, Myasthenia Gravis genetics, Myasthenia Gravis metabolism, Systems Biology methods
- Abstract
Background: About 5% of western populations are afflicted by autoimmune diseases many of which are affected by sex hormones. Autoimmune diseases are complex and involve many genes. Identifying these disease-associated genes contributes to development of more effective therapies. Also, association studies frequently imply genomic regions that contain disease-associated genes but fall short of pinpointing these genes. The identification of disease-associated genes has always been challenging and to date there is no universal and effective method developed., Results: We have developed a method to prioritize disease-associated genes for diseases affected strongly by sex hormones. Our method uses various types of information available for the genes, but no information that directly links genes with the disease. It generates a score for each of the considered genes and ranks genes based on that score. We illustrate our method on early-onset myasthenia gravis (MG) using genes potentially controlled by estrogen and localized in a genomic segment (which contains the MHC and surrounding region) strongly associated with MG. Based on the considered genomic segment 283 genes are ranked for their relevance to MG and responsiveness to estrogen. The top three ranked genes, HLA-G, TAP2 and HLA-DRB1, are implicated in autoimmune diseases, while TAP2 is associated with SNPs characteristic for MG. Within the top 35 prioritized genes our method identifies 90% of the 10 already known MG-associated genes from the considered region without using any information that directly links genes to MG. Among the top eight genes we identified HLA-G and TUBB as new candidates. We show that our ab-initio approach outperforms the other methods for prioritizing disease-associated genes., Conclusion: We have developed a method to prioritize disease-associated genes under the potential control of sex hormones. We demonstrate the success of this method by prioritizing the genes localized in the MHC and surrounding region and evaluating the role of these genes as potential candidates for estrogen control as well as MG. We show that our method outperforms the other methods. The method has a potential to be adapted to prioritize genes relevant to other diseases.
- Published
- 2008
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33. Transfusion triggers.
- Author
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Macpherson CR
- Subjects
- Health Services Needs and Demand, Humans, Blood Transfusion
- Published
- 1995
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34. Abnormal peri-operative haemorrhage in asymptomatic patients is not predicted by laboratory testing.
- Author
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Macpherson CR, Jacobs P, and Dent DM
- Subjects
- Aspirin adverse effects, Humans, Risk Factors, Blood Loss, Surgical prevention & control, Hematologic Tests, Preoperative Care
- Abstract
The pre-operative identification of individuals at high risk of bleeding during major elective surgery is obviously important. Extensive haemostatic screening is, however, expensive and may be inappropriate in low-risk groups. Accordingly, we undertook two studies to determine whether it could be justified in patients without a history of abnormal bleeding. In the first of these, 45 of 159 patients were excluded because of aspirin ingestion and a further 3 because of positive bleeding history so that prothrombin time, activated partial thromboplastin time, bleeding time and platelet count were measured in 111 asymptomatic patients about to undergo major surgery. A single patient had mild thrombocytopenia, and 8 had a prolonged partial thromboplastin time; none showed abnormal peri-operative haemorrhage. In the second study, over a 4-month period, 49 patients out of 1,872 required larger peri-operative blood transfusions than anticipated; on investigation, none of these patients was shown to have disturbances in haemostatic mechanism, the transfusion having been indicated for technical reasons. Patients undergoing elective surgery should be asked about medication and previous bleeding and if they have no history thereof and a physical examination is negative, pre-operative screening for coagulation defects would appear to be unnecessary.
- Published
- 1993
35. Reductio ad absurdum?
- Author
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Macpherson CR
- Subjects
- Blood Donors, Humans, Statistics as Topic, Blood Platelets, Fever etiology, Transfusion Reaction
- Published
- 1991
- Full Text
- View/download PDF
36. Sepsis associated with transfusion of red cells contaminated with Yersinia enterocolitica.
- Author
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Tipple MA, Bland LA, Murphy JJ, Arduino MJ, Panlilio AL, Farmer JJ 3rd, Tourault MA, Macpherson CR, Menitove JE, and Grindon AJ
- Subjects
- Adult, Aged, Aged, 80 and over, Blood Donors, Blood Preservation methods, Erythrocyte Transfusion, Erythrocytes microbiology, Female, Humans, Male, Middle Aged, Shock, Septic etiology, Yersinia enterocolitica, Transfusion Reaction, Yersinia Infections transmission
- Abstract
Between April 1987 and May 1989, the Centers for Disease Control investigated seven cases of transfusion-associated Yersinia enterocolitica sepsis; four were caused by organisms of serotype O:3, and one each was caused by organisms of serotype O:1,2,3; O:5,27; and O:20. All seven recipients developed septic shock after receiving units of red cells (RBCs) contaminated with Y. enterocolitica; five recipients died. The cases occurred in seven states and were unrelated. There was no evidence for contamination of the RBC units during processing. Six of the seven donors had serologic evidence of recent Y. enterocolitica infection, and it is hypothesized that these donors had asymptomatic bacteremia when they donated the implicated blood. Four of the seven donors reported gastrointestinal illness in the 4 weeks before blood donation, and one donor became ill on the day he donated blood. Y. enterocolitica grows well at 4 degrees C and in the presence of dextrose and iron. If blood is contaminated at the time of collection, storage of the RBCs at 4 degrees C provides an ideal environment for bacterial growth and endotoxin production. These cases demonstrate the need for careful evaluation of patients with transfusion reactions for possible sepsis and suggest a need to screen prospective blood donors for mild gastrointestinal illness, including those illnesses not requiring physician evaluation or medication.
- Published
- 1990
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37. Clinical value of lecithin and sphingomyelin determinations in amniotic fluid.
- Author
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Damoulaki-Sfakianaki E, De Walt C, Macpherson CR, and Cordero L
- Subjects
- Amniocentesis, Female, Humans, Infant, Newborn, Pregnancy, Amniotic Fluid analysis, Phosphatidylcholines analysis, Prenatal Diagnosis, Respiratory Distress Syndrome, Newborn diagnosis, Sphingomyelins analysis
- Published
- 1974
38. Bleeding time decreases with age.
- Author
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Macpherson CR and Jacobs P
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Sex Factors, Aging physiology, Bleeding Time, Platelet Function Tests
- Abstract
Template bleeding times were determined in 48 men and women under 50 years of age, and in 95 men and women over 50 years of age. There was no significant male/female difference in any age group, but there was a significant reduction in the bleeding time with increasing age in both men and women.
- Published
- 1987
39. Suggested blood bank curriculum for pathology residents.
- Author
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Macpherson CR, Davey RJ, Hooper GS, and Monaghan WP
- Subjects
- Blood Group Antigens, Blood Transfusion education, Workforce, Blood Banks organization & administration, Curriculum, Internship and Residency methods, Pathology, Clinical education
- Published
- 1983
- Full Text
- View/download PDF
40. Guidelines for an immunohematology/blood bank fellowship program.
- Author
-
Macpherson CR, Sherman LS, and Hooper GS
- Subjects
- Blood Transfusion, United States, Allergy and Immunology, Blood Banks, Fellowships and Scholarships, Hematology
- Published
- 1980
- Full Text
- View/download PDF
41. Routine admission testing.
- Author
-
Macpherson CR
- Subjects
- Costs and Cost Analysis, United States, Diagnostic Services economics, Hospitalization
- Published
- 1978
- Full Text
- View/download PDF
42. Human lymphocyte membrane immunoglobulin as a reflection of maturation.
- Author
-
James KK, Hurtubise PE, MacPherson CR, and Murphy SG
- Subjects
- Adolescent, Adult, Age Factors, Aged, Antibody Specificity, B-Lymphocytes immunology, Cell Membrane immunology, Cell Separation, Child, Child, Preschool, Hemagglutination Tests, Humans, Immune Sera, Immunodiffusion, Immunoglobulin G analysis, Immunoglobulin M analysis, Infant, Middle Aged, Binding Sites, Antibody, Lymphocytes immunology
- Published
- 1974
43. Enterobacteriaceae identification by MORLOC and API 20E.
- Author
-
Macpherson CR
- Subjects
- Bacteriological Techniques, Enterobacteriaceae isolation & purification
- Published
- 1976
44. Results of a Delphi poll to describe the necessary competencies of blood bank physicians.
- Author
-
Macpherson CR, Davey RJ, and Simpson MB
- Subjects
- Allied Health Personnel education, Blood Banks standards, Blood Donors, Blood Transfusion education, Humans, Inservice Training, Quality Control, Surveys and Questionnaires, United States, Blood Banks organization & administration, Clinical Competence standards, Physicians
- Published
- 1985
- Full Text
- View/download PDF
45. Oxygen therapy; an unsuspected source of hospital infections.
- Author
-
MACPHERSON CR
- Subjects
- Humans, Communicable Diseases transmission, Cross Infection, Disease Transmission, Infectious, Oxygen therapeutic use, Oxygen Inhalation Therapy
- Published
- 1958
- Full Text
- View/download PDF
46. Renal histochemistry in potassium depletion.
- Author
-
PEARSE AG and MACPHERSON CR
- Subjects
- Histocytochemistry, Hypokalemia, Kidney physiology, Potassium, Potassium Deficiency
- Published
- 1958
- Full Text
- View/download PDF
47. THE RH COMPLEX R1 (CDE).
- Author
-
LEWIS M, MACPHERSON CR, and GAYTON J
- Subjects
- Humans, Genetics, Medical, Rh-Hr Blood-Group System
- Published
- 1965
- Full Text
- View/download PDF
48. The hemolytic anemia of the Graft-versus-Host reaction in the chick, before and after hatching.
- Author
-
Macpherson CR and Deamer JC
- Subjects
- Animals, Poultry, Anemia, Hemolytic etiology, Antigen-Antibody Reactions, Transplantation Immunology
- Published
- 1965
- Full Text
- View/download PDF
49. Experimental investigation of secondary biliary strictures.
- Author
-
GOSWITZ JT, MACPHERSON CR, and ELLIOTT DW
- Subjects
- Constriction, Pathologic, Humans, Cholestasis, Common Bile Duct
- Published
- 1963
- Full Text
- View/download PDF
50. COPPER SULFATE SCREENING OF BLOOD DONORS: REPORT OF A DONOR PASSING THE TEST WITH LESS THAN EIGHT GRAMS OF HEMOGLOBIN.
- Author
-
MANNARINO AD and MACPHERSON CR
- Subjects
- Humans, Blood Donors, Blood Protein Electrophoresis, Copper, Copper Sulfate, Cyclophosphamide, Hemoglobinometry, Hemoglobins, Multiple Myeloma, Sulfates, Tissue Donors
- Published
- 1963
Catalog
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