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The local bonding environment of chlorine in silicate melts has a profound influence over the thermodynamic properties and structure of a melt, affecting the viscosity, rheology, and volatile degassing potential. To constrain the bonding environment of Cl in natural silicate melts, we have determined Cl K-edge X-ray absorption fine structure (XAFS) spectra for 44 experimentally produced silicate glasses in both the X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) regions. In the pre-edge region, the presence of a pre-edge peak indicates covalent bonding of chlorine with silicon. Addition of divalent cations suppresses this pre-edge feature, and its centroid shifts to higher energy, indicating a change to increasingly more ionic bonding. In the XANES region the main absorption edge energy, E0, and the energy of maximum intensity, EMax, are also compositionally dependent. SiO2- rich glasses have relatively low values of E0 and EMax while the addition of 2+ ions increases both to values close to those found in the end-member chlorides CaCl2, MgCl2, and FeCl2. In two Na-rich glasses, E0 and EMax are close to corresponding energies in NaCl. It appears, therefore that bonding in the glasses is closely related to that found in the simple chlorides. This may be due to clustering which generates Ca[sbnd]Cl, Mg[sbnd]Cl, Fe[sbnd]Cl and Na[sbnd]Cl linkages either in the melts themselves or in the glasses due to rearrangements during quenching. The EXAFS parts of the glass spectra confirm the conclusions derived from the XANES region. These show that, as expected from the XANES region, addition of Ca and Fe2+ leads to R-space peaks which are closely related to those found in anhydrous CaCl2 and FeCl2 respectively. In order to determine if the spectra depend on pressure, temperature or chlorine fugacity of synthesis, 9 experiments were conducted using a single starting composition (Fe-free haplobasalt, An50Di28Fo22) across a range of temperatures (1300–1400 °C), pressures (5–20 kbar), chlorine fugacities (f(Cl2)) (1.38E−03 to 1.66E−06), and water contents (expected 0–8 wt% H2O). The results show that there is almost no change in the spectra across the XANES and EXAFS regions, indicating either that chlorine bonding is independent of the intensive parameters of the experiment or that all melts quench to glasses with the same local structure around the Cl atoms.

High performance computing (HPC) workflows are undergoing tumultuous changes, including an explosion in size and complexity. Despite these changes, most batch job systems still use slow, centralized schedulers. Generalized hierarchical scheduling (GHS) solves many of the challenges that face modern workflows, but GHS has not been widely adopted in HPC. A major difficulty that hinders adoption is the lack of a performance model to aid in configuring GHS for optimal performance on a given application. We propose an analytical performance model of GHS, and we validate our proposed model with four different applications on a moderately-sized system. Our validation shows that our model is extremely accurate at predicting the performance of GHS, explaining 98.7% of the variance (i.e., an R2 statistic of 0.987). Our results also support the claim that GHS overcomes scheduling throughput problems; we measured throughput improvements of up to 270× on our moderately-sized system. We then apply our performance model to a pre-exascale system, where our model predicts throughput improvements of four orders of magnitude and provides insight into optimally configuring GHS on next generation systems.

Stickler syndrome (SS) is a genetic disorder with manifestations in the eye, ear, joints, face and palate. Usually inherited in a dominant fashion due to heterozygous pathogenic variants in the collagen genes COL2A1 and COL11A1, it can rarely be inherited in a recessive fashion from variants in COL9A1, COL9A2, and COL9A3, COL11A1, as well as the non-collagen genes LRP2, LOXL3 and GZF1. We review the published cases of recessive SS, which comprise 40 patients from 23 families. Both homozygous and compound heterozygous pathogenic variants are found. High myopia is near-universal, and sensorineural hearing loss is very common in patients with variants in genes for type IX or XI collagen, although hearing appears spared in the LRP2 and LOXL3 patients and is variable in GZF1. Cleft palate is associated with type XI collagen variants, as well as the non-collagen genes, but is so far unreported with type IX collagen variants. Retinal detachment has occurred in 18% of all cases, and joint pain in 15%. However, the mean age of this cohort is 11 years old, so the lifetime incidence of both problems may be underestimated. This paper reinforces the importance of screening for SS in congenital sensorineural hearing loss, particularly when associated with myopia, and the need to warn patients and parents of the warning signs of retinal detachment, with regular ophthalmic review.

The aim of this thesis is to understand the chemical behaviour of halogens in silicate melts by experimentally determining their thermodynamic activities. This includes defining how halogens become incorporated into a melt and what influences chlorine's solubility and bonding behaviour in silicate melts. A halogen buffer has been developed using Ag/AgCl, in which Ag (as oxide) is virtually insoluble in silicate melt under the conditions of the experiment. The buffer controls the fugacity of chlorine. Experiments were performed at 5-20 kbar and 1200-1500 °C in a piston-cylinder apparatus. The effect of oxygen fugacity on Cl solubility was determined using Re-ReO2 and C-CO2 oxygen buffers. Experiments show (1) that chlorine solubility in haplobasalt at 15 kbar/1400 °C can reach 5 wt%, even at Cl2 fugacities as low as 0.0035 bar. 2) Cl concentration increases linearly with the square root of chlorine fugacity at fixed f(O2), obeying Henry’s Law up to ~3% Cl in the melt of a haplobasalt. 3) Cl solubility decreases with the fourth root of oxygen fugacity at fixed √𝑓(𝐶𝑙2). This implies that Cl- replaces O2- in the silicate framework as follows: Cl2(gas)+[O2-](melt) = 2[Cl-](melt)+ ½O2(gas) [I] This relationship is used to correct for the effect of oxygen and chlorine fugacity on pressure and temperature, to determine more accurately how chlorine solubility changes with these intensive variables. Results show that Cl increases with temperature and decreases with pressure at fixed conditions. The chlorine buffering method was then applied to 44 chemically different compositions, all performed at 1400 °C, 15 kbar, and a fixed oxygen and chlorine fugacity. Results show that chlorine solubility increases with Ca and Fe and decreases with Si content. Knowing the compositional effects at fixed conditions allowed for the quantification of a chloride capacity (CCl), defined as: 𝐶𝐶𝑙= 𝐶𝑙 (𝑤𝑡%)√𝑓(𝐶𝑙2) ×√𝑓(𝑂2)4 [ii] The chlorine capacity allows for the comparison of literature data (including those performed with water) if the temperature, pressure, oxygen fugacity and chemical composition are known. Literature data were combined with the 44 experiments performed across a wide compositional range and the pressure and temperature series of experiments. Cl content in wt% can then be expressed as a function of the different variables as: 𝑙𝑜𝑔𝐶𝐶𝑙=0.571+(4873𝑋𝐶𝑎−3803𝑋𝑆𝑖+2724𝑋𝐹𝑒+1891- 943P)/T [iii] Water was found to be insignificant in controlling chlorine solubility at concentrations less than 4.3 wt%. [iii] can then be used to determine the conditions that HCl would degas. Results indicate that, at fixed Cl2 fugacity, pressure, and temperature most HCl loss occurs at pressures below 2 MPa. Additionally, the fraction lost as the surface is approached varies dramatically with composition as rhyolite>dacite>andesite>basalt. Constraining the thermodynamic activities also allows for determining the conditions under which Cl-rich minerals such as sodalite would form and when brines would begin to segregate from the melt. The bonding behaviour of chlorine in silicate melts was investigated by X-ray absorption fine structure. Results indicate that Cl predominantly bonds with 2+ cations (Ca, Mg and Fe) but can also covalently bond with Si in melts that exhibit low 2+ cation contents.

Therapy-related myeloid neoplasms (TMN) constitute one of the most challengingcomplications of cancer treatment.1 Whilst understanding of TMN pathogenesis remains fragmentary, genomic studies in adults have thus far refuted the notion that TMN simply result from cytotoxin-induced DNA damage.2–4 Analysis of the preclinical evolution of a limited number of adult TMN have retraced the majority of cases to clonal haematopoiesis (CH) that predates cytotoxic treatment and lacks the mutational footprint of genotoxic therapies.2–6 Balanced translocations, generally attributed to treatment with topoisomerase II inhibitors, are implicated in a minority of TMN.1 TMN is a leading cause of premature death in childhood cancer survivors, and affects 7-11% of children treated for high-risk neuroblastoma and sarcoma.7,8 However, the origin of pediatric TMN remains unclear. Targeted sequencing of known cancer genes detects CH in ~4% of children following cytotoxic treatment,6,9 whereas CH is vanishingly rare in young individuals in the general population.10,11 Moreover, to our knowledge, no cases of childhood TMN have been retraced to pretreatment CH. In light of these observations, we asked whether a broader driver landscape had eluded targeted CH screens in pediatric cancer patients and/or whether therapy-induced mutagenesis may be an under-recognised catalyst of CH and TMN in this patient group.

Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1, COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1. Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition.

Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference “cellular signals” in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of “fetalness” with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer., Transcriptomic analysis may provide information about the differentiation state and cell of origin of a cancer. Here, the authors assess mRNA signals in 1300 childhood and adult renal tumors and report a fetal origin of childhood tumors and no dedifferentiation of adult tumors.

Summary Background To date, epidemiological studies at the index site of the 2013–16 west African Ebola outbreak in Meliandou, Guinea, have been restricted in their scope. We aimed to determine the occurrence of previously undocumented Ebola virus disease (EVD) cases and infections, and to reconstruct transmission events. Methods This cross-sectional seroprevalence survey of the adult population of Meliandou used a highly specific oral fluid test and detailed interviews of all households in the village and key informants. Each household was interviewed, with all members prompted to describe the events of the outbreak, any illness within the household, and possible contact with suspected cases. Information for deceased individuals was provided by relatives living in the same household. Symptoms were based on Ebola virus Makona variant EVD case definitions (focusing on fever, vomiting, and diarrhoea). For antibody testing, we used an Ebola virus glycoprotein IgG capture enzyme immunoassay developed from a previously validated assay. A maximum exposure level was assigned to every participant using a predetermined scale. We used a generalised linear model (logit function) to estimate odds ratios for the association of sociodemographic variables and exposure level with Ebola virus infection. We adjusted estimates for age and maximum exposure, as appropriate. Findings Between June 22, and July 9, 2017, we enrolled 237 participants from 27 households in Meliandou. Two households refused to participate and one was absent. All adults in participating households who were present for the interview provided an oral fluid swab for testing, of which 224 were suitable for analysis. In addition to the 11 EVD deaths described previously, on the basis of clinical description and oral fluid testing, we found two probable EVD deaths and eight previously unrecognised anti-Ebola virus IgG-positive survivors, including one who had mild symptoms and one who was asymptomatic, resulting in a case fatality of 55·6% (95% CI 30·8–78·5) for adults. Health-care work (adjusted odds ratio 6·64, 1·54–28·56; p=0·001) and level of exposure (odds ratio adjusted for linear trend across five levels 2·79, 1·59–4·883; p

Tumor cells may produce many of the same messenger RNAs (mRNA) as the cell they derive from. The relative abundance of these mRNAs, the transcriptiomic profile, may provide clues into the origin and development of tumors. Here we investigated the cellular origins of 1,300 childhood and adult renal tumors, spanning 7 different subtypes. We decomposed tumor bulk transcriptomes into single cell components, measuring the abundance of single cell derived reference “cellular signals” in each tumor. We quantified the extent to which each tumor utilized fetal cellular signals, finding that all childhood renal tumors are definitively fetal. This replaces the long-held presumption of “fetalness” with a precise, quantitative readout of immaturity. Analyzing cellular signals in each tumor type, we recapitulated previous findings for some, whilst providing novel insights into other, less well understood tumor types. For example, our analyses predicted fetal interstitial cells as the cell of origin of the infant kidney tumor, congenital mesoblastic nephroma, and demonstrate that another childhood kidney cancer, malignant rhabdoid tumor, arises from mesodermally derived cells in early development. We found remarkable uniformity in the cell signal of each tumor type, indicating the possible therapeutic and diagnostic utility of cellular signal decomposition. We demonstrated this utility with an example of a child with a cryptic renal tumor, which had not been identifiable by conventional diagnostic work-up but was clearly classified with our approach. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.

Over the last decade, several devices for percutaneous nephrolithotomy with smaller diameters have been introduced in order to reduce renal trauma. Recent studies have found comparable stone free rates but also exhibit the same rate of postoperative fever and septicaemia. One possible cause is the influence of irrigation fluid during stone treatment procedures. The purpose of this ex vivo study was to compare two new miniaturised PNL nephroscopy sheaths with an outer sheath diameter of 9.5 F and 12 F to the well-established MIP M Set (17.5 F) by Karl Storz.The new devices were tested in a perfused organ model of fresh porcine kidneys with different irrigation pressures, applied either by gravitation or the use of a pressure pump (Uromat E.A.S.I. Pump, Karl Storz, Tuttlingen, Germany).In addition, the 9.5 F sheath was examined for active irrigation evacuation, i. e. suction of irrigation fluid through a mono-J-catheter. An urodynamic pressure probe measured intrapelvic pressure levels throughout the procedures.Regardless of the sheath diameters used, the intrapelvic pressure did not exceed 40 cmH The newly designed miniaturised MIP sets maintain the favourable pressure features of the earlier 17.5 MIP sheath. Although the diameter has been reduced to 12F or 9.5 F, the intrapelvic pressures remained below 40 cmH In den letzten Jahren wurde die Entwicklung miniaturisierter Amplatz-Schäfte für die perkutane Nephrolitholapaxie mit dem Ziel eines verringerten Nierentraumas vorangetrieben. Bisherige Studien konnten zwar vergleichbar gute Steinfreiheitsraten im Vergleich zur herkömmlichen PNL bestätigen, jedoch zeigten sich ebenfalls vergleichbare Häufigkeiten postoperativen Fiebers bzw. Septikämien. Als mögliche Ursache hierfür wird der Einfluss der intraoperativen intrapelvinen Drücke aufgrund verwendeter Spülung diskutiert. Ziel der vorliegenden Ex-vivo-Studie war der Vergleich der intrapelvinen Druckverhältnisse unter Verwendung der miniaturisierten 9,5 Ch- bzw. 12 Ch-Amplatz-Schäfte mit dem bereits voruntersuchten 17,5 Ch-MIP M-Schaft. MATERIAL UND METHODEN : Die Schäfte wurden an einem perfundierten Schweinenierenmodell frisch geschlachteter Schweine unter verschiedenen Perfusionsdrücken evaluiert. Der Spüldruck wurde zum einen über eine Spülpumpe (Uromat E.A.S.I. Pumpe, Karl Storz, Tuttlingen, Deutschland) oder per Schwerkraft erzeugt. Über einen transparenchymatös eingebrachten Urodynamikkatheter konnte der intrapelvine Druck kontinuierlich gemessen werden. Es wurden zusätzliche Analysen mit aktiver Flüssigkeitsabsaugung über einen einliegenden Ureterkatheter durchgeführt. ERGEBNISSE : Der intrapelvine Druck stieg in den Messungen mit moderaten Spüldruckverhältnissen sowohl durch Spülpumpe als auch durch Schwerkraft für beide Schaftgrößen nicht über 40 cmH

BACKGROUND: Endometrial cancer is one of the most common gynaecological cancers in the world. Rates of endometrial cancer are rising, in part because of rising obesity rates. Endometrial hyperplasia is a precancerous condition in women that can lead to endometrial cancer if left untreated. Endometrial hyperplasia occurs more commonly than endometrial cancer. Progesterone tablets currently used to treat women with endometrial hyperplasia are associated with adverse effects in up to 84% of women. The levonorgestrel intrauterine device (Mirena Coil, Bayer HealthCare Pharmaceuticals, Inc., Whippany, NJ, USA) may improve compliance, but it is invasive, is not acceptable to all women, and is associated with irregular vaginal bleeding in 82% of cases. Therefore, an alternative treatment for women with endometrial hyperplasia is needed. Metformin, a drug that is often used to treat people with diabetes, has been shown in some human studies to reverse endometrial hyperplasia. However, the effectiveness and safety of metformin for treatment of endometrial hyperplasia remain uncertain. OBJECTIVES: To determine the effectiveness and safety of metformin in treating women with endometrial hyperplasia. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, Google Scholar, OpenGrey, Latin American Caribbean Health Sciences Literature (LILACS), and two trials registers from inception to 10 January 2017. We searched the bibliographies of all included studies and reviews on this topic. We also handsearched the conference abstracts of the European Society of Human Reproduction and Embryology (ESHRE) 2015 and the American Society for Reproductive Medicine (ASRM) 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cross‐over trials comparing metformin (used alone or in combination with other medical therapies) versus placebo or no treatment, any conventional medical treatment, or any other active intervention for women with histologically confirmed endometrial hyperplasia of any type. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, extracted data from included studies, and assessed the risk of bias of included studies. We resolved disagreements by discussion or by deferment to a third review author. When study details were missing, review authors contacted study authors. The primary outcome of this review was regression of endometrial hyperplasia histology (with or without atypia) towards normal histology. Secondary outcome measures included recurrence of endometrial hyperplasia, progression of endometrial hyperplasia to endometrial cancer, hysterectomy rate, abnormal uterine bleeding, health‐related quality of life, and adverse effects during treatment. MAIN RESULTS: We included three RCTs in which a total of 77 women took part. We rated the quality of the evidence as very low for all outcomes owing to very serious risk of bias (associated with poor reporting, attrition, and limitations in study design) and imprecision. We performed a meta‐analysis of two trials with 59 participants. When metformin was compared with megestrol acetate in women with endometrial hyperplasia, we found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (odds ratio (OR) 3.34, 95% confidence interval (CI) 0.97 to 11.57, two RCTs, n = 59, very low‐quality evidence), hysterectomy rates (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 59, very low‐quality evidence), and rates of abnormal uterine bleeding (OR 0.91, 95% CI 0.05 to 15.52, two RCTs, n = 44 , very low‐quality evidence). We found no data for recurrence of endometrial hyperplasia or health‐related quality of life. Both studies (n = 59) provided data on progression of endometrial hyperplasia to endometrial cancer as well as one (n = 16) reporting some adverse effects in the metformin arm, notably nausea, thrombosis, lactic acidosis, abnormal liver and renal function among others. Another trial including 16 participants compared metformin plus megestrol acetate versus megestrol acetate alone in women with endometrial hyperplasia. We found insufficient evidence to determine whether there were differences between groups for the following outcomes: regression of endometrial hyperplasia histology towards normal histology (OR 9.00, 95% CI 0.94 to 86.52, one RCT, n = 16, very low‐quality evidence), recurrence of endometrial hyperplasia among women who achieve regression (OR not estimable, no events recorded, one RCT, n = 8, very low‐quality evidence), progression of endometrial hyperplasia to endometrial cancer (OR not estimable, no events recorded, one RCT, n = 13, very low‐quality evidence), or hysterectomy rates (OR 0.29, 95% CI 0.01 to 8.37, one RCT, n = 16, very low‐quality evidence). Investigators provided no data on abnormal uterine bleeding or health‐related quality of life. In terms of adverse effects, three of eight participants (37.5%) in the metformin plus megestrol acetate study arm reported nausea. AUTHORS' CONCLUSIONS: At present, evidence is insufficient to support or refute the use of metformin alone or in combination with standard therapy ‐ specifically, megestrol acetate ‐ versus megestrol acetate alone, for treatment of endometrial hyperplasia. Robustly designed and adequately powered randomised controlled trials yielding long‐term outcome data are needed to address this clinical question.

Partnerships have been a central feature of the tourism public policy landscape in advanced capitalist countries for some time. The intuitively appealing argument is that, by sharing expertise and decision making, commitment to the local tourism project is ensured. By participating in partnership working, small firms - which are almost universally characteristic of the sector - are said to contribute to the form and competitiveness of the tourism offer. Drawing on a variety of sources, this paper argues that in most cases such assertions are misplaced because 'partnerships' organized by the public sector are often predicated on an inadequate conceptualization of small firms in tourism, fail to appreciate the importance and complexity of informal economic relations, and usually ignore the particular power relations at play in local tourism policy formation and change.

A microbiological assay for determining lincomycin in swine feed, supplement, and a vitamin- mineral premix was studied collaboratively in 16 laboratories. The design of the study involved a complete feed, feed supplement, and a vitamin-mineral premix covering a range of fortification from 20 to 80 g/ton and 80 to 2600 g/ton. Two methods of sample preparation were used depending on the concentration of lincomycin in the sample. Statistical evaluation of the results from the 2 methods indicated that 10 and 11 collaborators, respectively, had mean recoveries which were not significantly different from one another. Ten laboratories obtained a mean recovery of 112.2% (range 102.3-123.5%) for the lower level, and 11 laboratories obtained a mean recovery of 104.4% (range 100.0-107.7%) for the higher level. The method has been adopted as official first action.

Funder: Max Williamson Fund, Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we study the relationship of histogenesis and clonal diversification in GCTs by analysing the genomes and transcriptomes of 547 microdissected histological units. We find no correlation between genomic and histological heterogeneity. However, we identify unifying features including the retention of fetal developmental transcripts across tissues, expression changes on chromosome 12p, and a conserved somatic evolutionary sequence of whole genome duplication followed by clonal diversification. While this pattern is preserved across all GCTs, the developmental timing of the duplication varies between prepubertal and postpubertal cases. In addition, tumours of younger children exhibit distinct substitution signatures which may lend themselves as potential biomarkers for risk stratification. Our findings portray the extensive diversification of GCT tissues and genetic subclones as randomly distributed, while identifying overarching transcriptional and genomic features.

Placentas can exhibit chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation—within a few cell divisions of the zygote—of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development. Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.