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In The Education of Clarence Three Stars Philip Burnham tells the life story of the remarkable Packs the Dog, a member of the Minneconjou Lakotas who was born in 1864 east of the Black Hills. His father, Yellow Knife, died when the boy was five, and the family eventually enrolled at Pine Ridge Agency with the Oglalas under an uncle's name, Three Stars. In 1879 Packs the Dog joined the first class of Indian students to be admitted to the Carlisle Indian Industrial School. An enthusiastic student, Clarence Three Stars, as he would come to be known, was one of five Lakota children who volunteered to stay at Carlisle after the three-year plan of instruction was finished-though he eventually left the school in frustration. Three Stars returned to Pine Ridge and married Jennie Dubray, another Carlisle veteran, and they had seven children. The life of Lakota advocate Three Stars spanned a time of dramatic change for Native Americans, from the pre-reservation period through the Dawes Act of 1887 until just before the Indian Reorganization Act of 1934. Three Stars was a teacher, interpreter, catechist, lawyer, and politician who lived through the federal policy of American Indian assimilation in its many guises, including boarding school education, religious conversion, land allotment, and political reorganization. He used the fundamentals of his own boarding school education to advance the welfare of the Oglala Lakota people, even when his efforts were deemed threatening or subversive. His dedication to justice, learning, and self-governance informed a distinguished career of classroom excellence and political advocacy on his home reservation of Pine Ridge.

Urinary tract infections are one of the most common infections in humans. Here we tested the utility of urinary cell-free DNA (cfDNA) to comprehensively monitor host and pathogen dynamics in bacterial and viral urinary tract infections. We isolated cfDNA from 141 urine samples from a cohort of 82 kidney transplant recipients and performed next-generation sequencing. We found that urinary cfDNA is highly informative about bacterial and viral composition of the microbiome, antimicrobial susceptibility, bacterial growth dynamics, kidney allograft injury, and host response to infection. These different layers of information are accessible from a single assay and individually agree with corresponding clinical tests based on quantitative PCR, conventional bacterial culture, and urinalysis. In addition, cfDNA reveals the frequent occurrence of pathologies that remain undiagnosed with conventional diagnostic protocols. Our work identifies urinary cfDNA as a highly versatile analyte to monitor infections of the urinary tract. Urinary tract infections are one of the most common infections in humans. Here, the authors use urinary cell-free DNA (cfDNA) to comprehensively monitor host and pathogen dynamics in bacterial and viral urinary tract infections, and show that it is a versatile analyte for monitoring urinary tract infections.

The origin of most bacterial infections in the urinary tract is often presumed to be the gut. Herein, we investigate the relationship between the gut microbiota and future development of bacteriuria and urinary tract infection (UTI). We perform gut microbial profiling using 16S rRNA gene deep sequencing on 510 fecal specimens from 168 kidney transplant recipients and metagenomic sequencing on a subset of fecal specimens and urine supernatant specimens. We report that a 1% relative gut abundance of Escherichia is an independent risk factor for Escherichia bacteriuria and UTI and a 1% relative gut abundance of Enterococcus is an independent risk factor for Enterococcus bacteriuria. Strain analysis establishes a close strain level alignment between species found in the gut and in the urine in the same subjects. Our results support a gut microbiota–UTI axis, suggesting that modulating the gut microbiota may be a potential novel strategy to prevent UTIs. Urinary tract infections (UTIs) are associated with changes in the gut microbiome. Here, the authors evaluate the relationship between the gut microbiome and development of UTI in kidney transplant patients and show that uropathogenic gut abundance might represent a risk factor for development of bacteriuria and UTI.

Solid organ transplantation remains the preferred treatment for many end-stage organ diseases, but complications due to acute rejection and infection occur frequently and undermine its long-term benefits. Monitoring of the health of the allograft is therefore a critically important component of post-transplant therapy. Here, we review several emerging applications of circulating cell-free DNA (cfDNA) in the post-transplant monitoring of rejection, infection, and immunosuppression. We further discuss the cellular origins and salient biophysical properties of cfDNA. A property of cfDNA that has been prominent since its discovery in the late 1940s is its ability to yield surprises. We review recent insights into the epigenetic features of cfDNA that yet again provide novel opportunities for transplant monitoring.

Circulating cell-free DNA (cfDNA) is emerging as a powerful monitoring tool in cancer, pregnancy and organ transplantation. Nucleosomal DNA, the predominant form of plasma cfDNA, can be adapted for sequencing via ligation of double-stranded DNA (dsDNA) adapters. dsDNA library preparations, however, are insensitive to ultrashort, degraded cfDNA. Drawing inspiration from advances in paleogenomics, we have applied a single-stranded DNA (ssDNA) library preparation method to sequencing of cfDNA in the plasma of lung transplant recipients (40 samples, six patients). We found that ssDNA library preparation yields a greater portion of sub-100 bp nuclear genomic cfDNA ( p 10 −5 , Mann-Whitney U Test), and an increased relative abundance of mitochondrial (10.7x, p 10 −5 ) and microbial cfDNA (71.3x, p 10 −5 ). The higher yield of microbial sequences from this method increases the sensitivity of cfDNA-based monitoring for infections following transplantation. We detail the fragmentation pattern of mitochondrial, nuclear genomic and microbial cfDNA over a broad fragment length range. We report the observation of donor-specific mitochondrial cfDNA in the circulation of lung transplant recipients. A ssDNA library preparation method provides a more informative window into understudied forms of cfDNA, including mitochondrial and microbial derived cfDNA and short nuclear genomic cfDNA, while retaining information provided by standard dsDNA library preparation methods.

Beard was not only a witness to two major battles against the Lakota; he also traveled with William \"Buffalo Bill\" Cody's Wild West show, worked as a Hollywood Indian, and witnessed the grand transformation of the Black Hills into a tourism mecca. Beard spent most of his later life fighting to reclaim his homeland and acting as \"old Dewey Beard,\" a living relic of the \"old West\" for the tourists.

Tuberculosis (TB) remains a significant cause of mortality worldwide. Metagenomic next-generation sequencing has the potential to reveal biomarkers of active disease, identify coinfection, and improve detection for sputum-scarce or culture-negative cases. We conducted a large-scale comparative study of 428 plasma, urine, and oral swab samples from 334 individuals from TB endemic and non-endemic regions to evaluate the utility of a shotgun metagenomic DNA sequencing assay for tuberculosis diagnosis. We found that the composition of the control population had a strong impact on the measured performance of the diagnostic test: the use of a control population composed of individuals from a TB non-endemic region led to a test with nearly 100% specificity and sensitivity, whereas a control group composed of individuals from TB endemic regions exhibited a high background of nontuberculous mycobacterial DNA, limiting the diagnostic performance of the test . Using mathematical modeling and quantitative comparisons to matched qPCR data, we found that the burden of Mycobacterium tuberculosis DNA constitutes a very small fraction (0.04 or less) of the total abundance of DNA originating from mycobacteria in samples from TB endemic regions. Our findings suggest that the utility of a minimally invasive metagenomic sequencing assay for pulmonary tuberculosis diagnostics is limited by the low burden of M. tuberculosis and an overwhelming biological background of nontuberculous mycobacterial DNA .

Circulating tumor DNA (ctDNA) is a promising diagnostic marker for many cancers and can be noninvasively assayed from blood. For diagnosing glioma, this approach has unfortunately proven to be of limited use since glioma contribute minimal ctDNA to the blood circulation. A more promising avenue may therefore be to hunt for ctDNA in cerebrospinal fluid (CSF). The study by Mouliere et al in this issue of EMBO Molecular Medicine demonstrates that shallow whole‐genome sequencing of CSF‐cfDNA can be used to detect copy number alterations in glioma‐derived ctDNA, providing a low cost strategy to screen for glioma. Graphical Abstract De Vlaminck & colleagues discuss the low‐cost screening strategy developed by Mouliere et al (in this issue of EMBO Molecular Medicine ) that takes advantage of shallow whole‐genome sequencing of tumor‐derived cell‐free DNA in the cerebrospinal fluid to identify gliomas.

Background Cell-free DNA (cfDNA) in blood, urine, and other biofluids provides a unique window into human health. A proportion of cfDNA is derived from bacteria and viruses, creating opportunities for the diagnosis of infection via metagenomic sequencing. The total biomass of microbial-derived cfDNA in clinical isolates is low, which makes metagenomic cfDNA sequencing susceptible to contamination and alignment noise. Results Here, we report low biomass background correction (LBBC), a bioinformatics noise filtering tool informed by the uniformity of the coverage of microbial genomes and the batch variation in the absolute abundance of microbial cfDNA. We demonstrate that LBBC leads to a dramatic reduction in false positive rate while minimally affecting the true positive rate for a cfDNA test to screen for urinary tract infection. We next performed high-throughput sequencing of cfDNA in amniotic fluid collected from term uncomplicated pregnancies or those complicated with clinical chorioamnionitis with and without intra-amniotic infection. Conclusions The data provide unique insight into the properties of fetal and maternal cfDNA in amniotic fluid, demonstrate the utility of cfDNA to screen for intra-amniotic infection, support the view that the amniotic fluid is sterile during normal pregnancy, and reveal cases of intra-amniotic inflammation without infection at term. 7ESvei6brGwyYZ7yuuRbtx Video abstract.

Their first months at Carlisle were agony. Most of the students were homesick and hungry. The moon rose and set in the same sky, but the months had different names now. The trees were bare, the air biting. The temptation to resist was strong, especially among the older boys. In the eyes of his warders, Packs the Dog, now known as Clarence, was an unkempt, uncivilized, unfinished specimen of a boy. That first year he became known as a troublemaker. He was smart and good with numbers, a skill that would stand him well in later life, and one day