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"Lee, John R."
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Almost human : the astonishing tale of Homo naledi and the discovery that changed our human story
\"In 2013, Lee Berger ... caught wind of a cache of bones in a hard-to-reach underground cave in South Africa. He put out a call around the world for petite collaborators--men and women small and adventurous enough to be able to squeeze through 8-inch tunnels to reach a sunless cave 40 feet underground. With this team of 'underground astronauts,' Berger made the discovery of a lifetime: hundreds of prehistoric bones, including entire skeletons of at least 15 individuals, all perhaps two million years old. Their features combined those of known prehominids like Lucy, the famous Australopithecus, with those more human than anything ever before seen in prehistoric remains\"-- Provided by publisher.
Book
Gut Microbiota and Tacrolimus Dosing in Kidney Transplantation
Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2 ± 1.1 mg/day vs. 3.8 ± 0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6 ± 2.4 mg/day vs. 3.3 ± 1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient ± standard error of 1.0 ± 0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels.
Journal Article
Cave of bones : a true story of discovery, adventure, and human origins
\"This thrilling book takes the reader into South African caves to discover fossil remains that reframe the human family tree\"-- Provided by publisher.
Book
Detection of infiltrating fibroblasts by single-cell transcriptomics in human kidney allografts
We tested the hypothesis that single-cell RNA-sequencing (scRNA-seq) analysis of human kidney allograft biopsies will reveal distinct cell types and states and yield insights to decipher the complex heterogeneity of alloimmune injury. We selected 3 biopsies of kidney cortex from 3 individuals for scRNA-seq and processed them fresh using an identical protocol on the 10x Chromium platform; (i) HK: native kidney biopsy from a living donor, (ii) AK1: allograft kidney with transplant glomerulopathy, tubulointerstitial fibrosis, and worsening graft function, and (iii) AK2: allograft kidney after successful treatment of active antibody-mediated rejection. We did not study T-cell-mediated rejections. We generated 7217 high-quality single cell transcriptomes. Taking advantage of the recipient-donor sex mismatches revealed by X and Y chromosome autosomal gene expression, we determined that in AK1 with fibrosis, 42 months after transplantation, more than half of the kidney allograft fibroblasts were recipient-derived and therefore likely migratory and graft infiltrative, whereas in AK2 without fibrosis, 84 months after transplantation, most fibroblasts were donor-organ-derived. Furthermore, AK1 was enriched for tubular progenitor cells overexpressing profibrotic extracellular matrix genes. AK2, eight months after successful treatment of rejection, contained plasmablast cells with high expression of immunoglobulins, endothelial cell elaboration of T cell chemoattractant cytokines, and persistent presence of cytotoxic T cells. In addition to these key findings, our analysis revealed unique cell types and states in the kidney. Altogether, single-cell transcriptomics yielded novel mechanistic insights, which could pave the way for individualizing the care of transplant recipients.
Journal Article
A metagenomic DNA sequencing assay that is robust against environmental DNA contamination
Metagenomic DNA sequencing is a powerful tool to characterize microbial communities but is sensitive to environmental DNA contamination, in particular when applied to samples with low microbial biomass. Here, we present Sample-Intrinsic microbial DNA Found by Tagging and sequencing (SIFT-seq) a metagenomic sequencing assay that is robust against environmental DNA contamination introduced during sample preparation. The core idea of SIFT-seq is to tag the DNA in the sample prior to DNA isolation and library preparation with a label that can be recorded by DNA sequencing. Any contaminating DNA that is introduced in the sample after tagging can then be bioinformatically identified and removed. We applied SIFT-seq to screen for infections from microorganisms with low burden in blood and urine, to identify COVID-19 co-infection, to characterize the urinary microbiome, and to identify microbial DNA signatures of sepsis and inflammatory bowel disease in blood.
The accuracy of metagenomic DNA sequencing is limited by environmental DNA contamination. Here, the authors develop and test SIFT-seq, a metagenomic DNA sequencing assay that allows to identify and remove environmental DNA contamination introduced during sample preparation.
Journal Article
The fall of Númenor : and other tales from the second age of Middle-Earth
J.R.R. Tolkien famously described the Second Age of Middle-earth as a dark age, and not very much of its history is (or need be) told. And for many years readers would need to be content with the tantalizing glimpses of it found within the pages of The Lord of the Rings and its appendices, including the forging of the Rings of Power, the building of the Barad-dûr and the rise of Sauron. It was not until Christopher Tolkien published The Silmarillion after his father's death that a fuller story could be told. Although much of the book's content concerned the First Age of Middle-earth, there were at its close two key works that revealed the tumultuous events concerning the rise and fall of the island of Númenor. Raised out of the Great Sea and gifted to the Men of Middle-earth as a reward for aiding the angelic Valar and the Elves in the defeat and capture of the Dark Lord Morgoth, the kingdom became a seat of influence and wealth; but as the Númenóreans' power increased, the seed of their downfall would inevitably be sown, culminating in the Last Alliance of Elves and Men. Even greater insight into the Second Age would be revealed in subsequent publications, first in Unfinished Tales of Númenor and Middle-earth, then expanded upon in Christopher Tolkien's magisterial twelve-volume The History of Middle-earth, in which he presented and discussed a wealth of further tales written by his father, many in draft form. Now, adhering to the timeline of The Tale of Years in the appendices to The Lord of the Rings, editor Brian Sibley has assembled into one comprehensive volume a new chronicle of the Second Age of Middle-earth, told substantially in the words of Tolkien from the various published texts, with new illustrations in watercolor and pencil by the doyen of Tolkien art, Alan Lee.
Book
A quantitative comparison of urine centrifugation and filtration for the isolation and analysis of urinary nucleic acid biomarkers
Urine is a rich source of nucleic acid biomarkers including cell-free DNA (cfDNA) and RNA for monitoring the health of kidney allografts. In this study, we aimed to evaluate whether urine filtration can serve as an alternative to the commonly used method of centrifugation to collect urinary fluid and cell pellets for isolating cfDNA and cellular messenger RNA (mRNA). We collected urine specimens from kidney allograft recipients and obtained the urine supernatant and cell pellet from each specimen using both filtration and centrifugation for paired analyses. We performed DNA sequencing to characterize the origin and properties of cfDNA, as well as quantitative PCR of mRNAs extracted from cell fractions. Our results showed that the biophysical properties of cfDNA, the microbial DNA content, and the tissues of origin of cfDNA were comparable between samples processed using filtration and centrifugation method. Similarly, mRNA quality and quantity obtained using both methods met our criteria for downstream application and the Ct values for each mRNA were comparable between the two techniques.The Ct values demonstrated a high degree of correlation. These findings suggest that urine filtration is a viable alternative to urine centrifugation for isolation of nucleic acid biomarkers from urine specimens.
Journal Article
The fall of Gondolin
\"The final work of J.R.R. Tolkien's Middle-earth fiction, completing Christopher Tolkien's life-long achievement as the editor and curator of his father's manuscripts\"-- Provided by publisher.
Book
Exome Sequencing and Prediction of Long-Term Kidney Allograft Function
Current strategies to improve graft outcome following kidney transplantation consider information at the human leukocyte antigen (HLA) loci. Cell surface antigens, in addition to HLA, may serve as the stimuli as well as the targets for the anti-allograft immune response and influence long-term graft outcomes. We therefore performed exome sequencing of DNA from kidney graft recipients and their living donors and estimated all possible cell surface antigens mismatches for a given donor/recipient pair by computing the number of amino acid mismatches in trans-membrane proteins. We designated this tally as the allogenomics mismatch score (AMS). We examined the association between the AMS and post-transplant estimated glomerular filtration rate (eGFR) using mixed models, considering transplants from three independent cohorts (a total of 53 donor-recipient pairs, 106 exomes, and 239 eGFR measurements). We found that the AMS has a significant effect on eGFR (mixed model, effect size across the entire range of the score: -19.4 [-37.7, -1.1], P = 0.0042, χ2 = 8.1919, d.f. = 1) that is independent of the HLA-A, B, DR matching, donor age, and time post-transplantation. The AMS effect is consistent across the three independent cohorts studied and similar to the strong effect size of donor age. Taken together, these results show that the AMS, a novel tool to quantify amino acid mismatches in trans-membrane proteins in individual donor/recipient pair, is a strong, robust predictor of long-term graft function in kidney transplant recipients.
Journal Article