Pasuchaca (Geranium dielsianum Knuth), a traditional Peruvian medicinal plant from the Geraniaceae family used for diabetes management, was investigated for its antiglycative properties. This study aimed to screen, isolate, and identify the active antiglycative compounds from its aerial parts. By coupling a methylglyoxal (MGO)-HPLC screening assay with high-speed counter-current chromatography (HSCCC), seven dihydroflavonol derivatives were separated and identified from the 80% methanol extract. The compounds were identified as 2,3-dihydromyricetin 3-O-α-rhamnopyranoside (1), (+)-taxifolin 3-O-β-D-xylopyranoside (2), astilbin (6), isoastilbin (8), 3″-acetyl astilbin (9), and 2″-acetyl astilbin (11). Astilbin was identified as the major constituent, with remarkably high contents of 252.41 mg/g in the 80% methanol extract and 541.04 mg/g in the partitioned upper layer fraction. Astilbin demonstrated potent antiglycation activity across all stages of protein glycation (early, middle, late, and whole stages), significantly surpassing the positive control aminoguanidine. Furthermore, the formation of MGO-astilbin adducts was confirmed by LC-ESI-MS, validating its role as an effective MGO scavenger. This report is the first to isolate these phytochemicals from Pasuchaca. The findings establish astilbin as the key antiglycative component of Pasuchaca, substantiating its traditional use and highlighting its potential as a source of functional food ingredients or natural therapeutics for mitigating glycative stress.
The emerging alien cactus Cylindropuntia pallida (Rose) F.M. Knuth originates from northern Mexico and introduced into South Africa in 1940s as an ornamental plant.  Multiple populations of C. pallida have been detected in various areas of South Africa. C. pallida has effective propagule dispersal and rapid recruitment making it a likely key future invader, and thus, is a target for eradication in South Africa. To eradicate C. pallida populations, a foliar spray (i.e. using a 2% concentration of herbicide with fluroxypyr and triclopyr) has been applied to plants in nine populations, with population sizes ranging between 535 and 2701 plants and populations covering areas of 100 -1000 ha. The aims of the study were to investigate the efficacy of the foliar spray method used to eradicate C. pallida; to investigate the impacts of C. pallida invasions on native vegetation integrity; to apply species distribution models (SDMs) to identify suitable climates for C. pallida in South Africa; and to document the biomes vulnerable to the negative impact of C. pallida in South Africa. Results show that foliar spray killed many C. pallida plants (mean percentage of dead plants ± SE, 83.3 ± 6.4; n = 9; range, 70-96%), with adult plants taking about 2 months to die completely. The efficacy of the herbicide was not affected by plant size or the concentration of the herbicide used. The invaded site had significantly greater vegetation cover which persisted across winter compared to the uninvaded site, but the latter site's vegetation cover significantly dropped in winter. Also, the invaded site had lower plant species diversity than the uninvaded site and was dominated by species in the Poaceae and Asteraceae plant families. Additionally, a normalised difference vegetation index (NDVI) analysis shows that the uninvaded site has higher vegetation cover and health than the invaded site wherein a notable decline in vegetation health was observed between 2019 and 2022. A large area (> 15 million hectares) was predicted to be suitable for invasion by C. pallida in provinces with arid and warm temperate climates - the fynbos and grassland biomes are the most vulnerable. Because of the observed negative impacts, high environmental compatibility, and high cost of clearing large infestations, we advocate for considering the biocontrol method for effectively managing C. pallida invasion in South Africa.
As a rare and endangered species, Primula filchnerae Knuth faces high seedling-stage mortality that likely contributes significantly to its threatened status. The study aims to investigate the effects of different light intensities under controlled conditions on the photosynthetic traits of P. filchnerae seedlings, elucidate its mechanism of light response and identify optimal light environments for seedlings survival, thereby providing a basis for scientific protection. The three light-intensity treatments were established through artificial shading to simulate the constant light intensity of natural habitat conditions observed in the field: intermediate light intensity (L1, 162 µmol·m⁻²·s⁻¹, control), semi-open area (L2, 324 µmol·m⁻²·s⁻¹) and understory (L3, 5.4 µmol·m⁻²·s⁻¹). Our study revealed that P. filchnerae seedlings exhibited significantly reduced Pnmax and PIABS under both L2 and L3 treatments relative to L1. Specifically, the decrease in photosynthetic rate under L2 was caused by stomatal limitation, while that under L3 was induced by non-stomatal limitation. In contrast, P. filchnerae seedlings maintained high antioxidant enzyme activity and stable accumulation of osmoregulatory substances in L1 treatment. Transcriptomic profiling indicated that flavonoid biosynthesis pathway genes were highly expressed under L2 compared to L1, while photosynthesis-related genes were downregulated under L3 condition. Based on the findings, the L1 treatment represents the optimal growth condition for P. filchnerae seedlings, where photosynthetic efficiency, light energy utilization capacity and stress resistance achieve their most favorable synergistic state. In contrast, both the L2 and L3 conditions were shown to be suboptimal, adversely affecting seedlings growth and physiological performance.
Recurrence originating from the saphenofemoral junction (SFJ) after an open surgical approach to or endovenous ablation of the great saphenous vein frequently occurs. The optimal treatment for a saphenofemoral recurrence remains a subject of debate. Currently, open redo surgery is becoming less common. This study analyzes the long-term effectiveness of saphenofemoral redo surgery following the principles of a modern surgical approach. Patients who underwent saphenofemoral reoperation in 2015 and 2016 were identified retrospectively and invited to participate in a prospective follow-up examination. Redo surgery was performed under general and additional tumescent local anesthesia as inpatient treatment and included flush religation of the SFJ , stump suture, cauterization of the free endothelium, and removal of neovascularization. The following objectives were analyzed: Duplex ultrasound-detectable recurrent reflux at the SFJ, clinical recurrence according to Recurrent Varices After Surgery classification, disease severity and quality of life using standardized protocols (Revised Venous Clinical Severity Score, Homburg Varicose Vein Severity Score, Chronic Venous Insufficiency Questionnaire), and patient-reported satisfaction. A total of 84 patients (94 treated legs) were included with a median follow-up of 6.6 years. Five of the 94 legs (5.3%) had a duplex-detected reflux in the groin, with only 1 leg (1.1%) showing grade 2 neovascularization (vessel diameter of ≥4 mm). According to Recurrent Varices After Surgery classification, 2 of the 94 legs (2.1%) revealed clinical recurrence arising from the inguinal region. Disease severity at follow-up was low with a mean Revised Venous Clinical Severity Score(0-30) of 1.8 ± 1.8 and a mean Homburg Varicose Vein Severity Score (0-33) of 3.9 ± 3.4. According to the Clinical, Etiological, Anatomical and Pathological classification, the stage of disease improved significantly (P < .001) in 55% of the treated legs. The procedure was well-accepted by patients: 94.1% indicated they would undergo saphenofemoral reoperation again if medically advised. This study demonstrates that saphenofemoral redo surgery is very effective when certain technical strategies are implemented to prevent neovascularization. Long-term treatment results may be superior to minimally invasive procedures, indicating the need for comparative studies. Until such studies are available, open redo surgery should continue to be considered as an appropriate treatment option for saphenofemoral recurrence.
Since February 2022, the war in Ukraine has led to large-scale displacement, including people living with HIV (PLWH). Early reports described predominantly virologically suppressed individuals with preserved immune function. Data on refugees with HIV presenting during later phases of the war are limited. We conducted a retrospective single-center study including adult refugees with HIV from Ukraine presenting to a tertiary care center in Germany. Paticipants were grouped by time of presentation: Cohort 1 (March-December 2022) and Cohort 2 (January 2023-February 2024). Clinical, immunological, and virological parameters were compared between cohorts. A total of 86 individuals were included (Cohort 1: n = 46; Cohort 2: n = 40). Participants in cohort 2 more frequently received their first HIV diagnosis after presentation in Germany, with no previously documented HIV diagnosis in Ukraine or elsewhere, compared with cohort 1 (67% vs. 5%; p < 0.0001). Participants in Cohort 2 more often presented with detectable HIV RNA (65% vs. 29%; p < 0.0001) and advanced immunodeficiency (CD4 < 200/µL: 28% vs. 9%; p < 0.05). Among individuals with prior HIV diagnosis, virological failure was more common in Cohort 2 (50% vs. 14%; p = 0.006). AIDS-defining illnesses occurred more frequently in Cohort 2 (p = 0.005). Serological evidence of HBV and HCV infection was high in both cohorts. Refugees with HIV from Ukraine presenting during later phases of the war exhibit more advanced disease and poorer virological control compared with earlier arrivals. These findings suggest increasing disruption of HIV care over time and highlight the need for low-threshold access to testing, comprehensive screening, and rapid initiation of antiretroviral therapy in this population.
To better understand large-effect pathogenic variation associated with autism, we generated long-read sequencing (LRS) data to construct phased and near-complete genome assemblies (average contig N50 = 43 Mbp, QV = 56) for 189 individuals from 51 families with unsolved cases. We applied read- and assembly-based strategies to facilitate comprehensive characterization of de novo mutations, structural variants (SVs), and DNA methylation. Using LRS pangenome controls, we efficiently filtered >97% of common SVs exclusive to 87 offspring. We find no evidence of increased autosomal SV burden for probands when compared to unaffected siblings yet observe a suggestive trend toward an increased SV burden on the X chromosome among affected females. We establish a workflow to prioritize potential pathogenic variants by integrating autism risk genes and putative noncoding regulatory elements defined from ATAC-seq and CUT&Tag data from the developing cortex. In total, we identified three pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, as well as nine candidate de novo and biallelic inherited homozygous SVs, most of which were missed by short-read sequencing. Our work highlights the potential of phased genomes to discover complex more pathogenic mutations and the power of the pangenome to restrict the focus on an increasingly smaller number of SVs for clinical evaluation.
A specific and accurate blood test for acute brain injury could help monitor infarct growth in ischemic stroke and serve as a surrogate end point in clinical trials. Using a single-molecule detection assay, we assessed plasma brain-derived tau (BD-tau), a marker selectively quantifying tau protein from the central nervous system, in a prospective cohort of 502 patients with acute ischemic stroke with serial blood sampling from admission to day 7. Higher BD-tau concentrations at admission were associated with more extensive early brain injury on computed tomography and predicted larger final infarct volumes. BD-tau increases from admission to day 2 were related to infarct growth. BD-tau concentrations rose until day 7 and were higher in patients with secondary events, including recurrent stroke. After thrombectomy, the rise of BD-tau was smaller in patients with complete versus incomplete recanalization. BD-tau outperformed other blood markers and imaging metrics in predicting 90-day functional outcome across infarct size strata and time points. In an independent multicenter prospective cohort (N = 519), BD-tau showed higher performance than magnetic resonance imaging-derived final infarct volume in predicting functional outcomes at 3, 12, and 36 months. In the biomarker substudy of a phase 3 trial assessing nerinetide in patients with ischemic stroke (N = 193), BD-tau showed predictive performance comparable to the other cohorts, mediated the relationship between recanalization and functional outcome, and showed a 49% smaller increase in the nerinetide group versus placebo. Overall, plasma BD-tau tracked ischemic brain injury over time, outperformed other biomarkers in predicting functional outcomes, and identified possible treatment responses.
To describe the prevalence of physical activity and assess its correlation with a unidimensional economic measure (per capita gross domestic product - GDP) and a multidimensional measure of countries' fragility (Fragile States Index). Physical activity was measured using data from STEPwise Approach to Noncommunicable Disease Risk-Factor Surveillance calculated at individual level. We obtained the following indicators: total physical activity, any leisure-time, any transport and any work physical activity. GDP and FSI were obtained from the World Bank and the Fund for Peace respectively. An analysis was carried out to verify the relationship between physical activity and GDP/FSI. We included data from 51 countries. The prevalence of meeting physical activity recommendations was 82.6%, while for any leisure-time, any transportation and any work, the proportions were 23.6%, 73.0% and 60.5%, respectively. For any leisure-time physical activity, the lower the prevalence of the outcome the higher the fragility of countries (r = -0.55). In contrast, for any work physical activity, the pattern was inverse (r = 0.35). Our results underscore the relevance of contextual correlates of domain-specific physical activity and emphasise the need to reconsider the meaning of physical activity in each location, accounting for its different domains in promotion efforts.
Understanding the public health impact of women's health research is crucial for improving health outcomes and guiding future research priorities. Bibliometric analysis offers a unique suite of tools to identify opportunities to increase impact and measure the dissemination of women's health research. Using 2018-2021 mortality data from the National Vital Statistics System, we utilized age-adjusted death rates to identify conditions with the highest relative mortality risk for females versus males. Our analysis showed that breast cancer, Alzheimer's disease, infections of the kidney, and acute rheumatic fever and chronic rheumatic heart diseases were associated with the highest relative mortality risk for females. Using a systematic keyword search strategy, we identified 219 Centers for Disease Control and Prevention (CDC)-authored publications published between 2018 and 2023 featuring these conditions in a database of CDC-authored publications. For relevant publications on each condition, we evaluated five bibliometric indicators measuring media attention, academic citations, and policy citations. Overall, CDC's publications on these conditions did not demonstrate a gap in media attention, academic citations, and policy citations compared with other agency publications, underscoring the agency's effectiveness in disseminating its research on these topics. Assessing bibliometric indicators for published research on conditions with disproportionate relative mortality risk for females can reveal potential gaps in research coverage, highlight research successes, and inform strategic decisions for disseminating women's health research.
Reactive oxygen species modulator 1 (ROMO1) is a highly conserved inner mitochondrial membrane protein that senses reactive oxygen species and regulates mitochondrial dynamics. ROMO1 is required for mitochondrial fusion in vitro, and silencing ROMO1 increases sensitivity to cell death stimuli. The physiological role of ROMO1 remains unclear. To determine the role of Romo1 in vivo, we used gene targeting in mice to ablate Romo1 in the whole mouse and to conditionally knock out Romo1 in the pancreatic beta cell. Mitochondrial functional analyses were performed on isolated mouse and human islets lacking Romo1/ROMO1. We show that ROMO1 is essential for embryonic development, as Romo1 null mice die before embryonic day 8.5, earlier than GTPases OPA1 or MFN1/2 which catalyse mitochondrial inner and outer membrane fusion. Knockout of Romo1 in adult pancreatic beta cells results in impaired glucose homeostasis in young male mice (4 months) due to an insulin secretion defect. Isolated islets from male, but not female, mice showed impaired glucose-stimulated insulin secretion. While mitochondria from female mice were morphologically normal, mitochondria in Romo1 adult beta cell knockout (RABKO) cells from male mice were swollen and fragmented, with a reduction in mtDNA content. Knockout of Romo1 did not affect basal respiration in males or females, but deletion of Romo1 in both sexes in mice and of ROMO1 in isolated human islets reduced spare respiratory capacity, which involved the specific loss of respiratory activity at complex II/succinate dehydrogenase. Ageing of female RABKO mice resulted in loss of spare respiratory capacity and glucose intolerance. Our data demonstrate that ROMO1 is a key regulator of mitochondrial bioenergetics and spare respiratory capacity and is required for effective nutrient coupling to insulin secretion in the beta cell. These observations point to a critical role for spare respiratory capacity in the maintenance of euglycaemia and to the potential for targeting ROMO1/complex II to promote glucose coupling in settings of insulin insufficiency.
Cryospheric landforms play a critical role in alpine hydrology and ecosystems. Using historical and contemporary data spanning nearly six decades (1967-2024), we assessed elevation change for glaciers, rock glaciers, and perennial snowfields and the thermal response of streams in the Teton Range, Wyoming, United States. Glaciers and snowfields thinned at -0.84 ± 0.07 meters per year (m year-1) and -0.59 ± 0.04 m year-1 between 2014 and 2022, a ~7-fold increase relative to 1967-2014, driven by warming summer temperatures. In contrast, rock glaciers are near equilibrium (-0.05 ± 0.05 m year-1) and saw no change in rate. Since 2015, snowfield-fed streams have warmed rapidly (+3.4°C), whereas glacier- and rock glacier-fed streams have warmed at lower magnitudes (+0.9° and +0.6°C, respectively). Our results demonstrate the greater resilience of rock glaciers to atmospheric warming, highlighting the critical role that these features will play as glaciers and perennial snowfields are lost.
The design of low-complexity and efficient constrained codes has been a major research item for many years. This paper reports on a versatile method named concatenated constrained codes for designing efficient fixed-length constrained codes with small complexity. A concatenated constrained code comprises two (or more) cooperating constrained codes of low complexity enabling long constrained codes that are not practically feasible with prior art methods. We apply the concatenated coding approach to two case studies, namely the design of constant-weight and low-weight codes. In a binary constant-weight code, each codeword has the same number, w, of 1's, where w is called the weight of a codeword. We specifically focus on the trading between coder complexity and redundancy.
The tumor immune microenvironment (TIME) shows significant heterogeneity in primary clear cell renal cell carcinoma (ccRCC). As TIME heterogeneity between primary and paired metastatic tumors of ccRCC is less understood, we characterized and compared the TIME of primary ccRCC with paired asynchronous metastases. We analyzed patients who developed ccRCC recurrence post radical nephrectomy and had both primary and metastatic treatment-naïve tissue available. Capture whole-transcriptome sequencing was performed on formalin-fixed paraffin-embedded (FFPE) specimens using the Illumina platform. Differential gene expression (DGE) analysis and gene set enrichment analysis (GSE) was performed using R packages limma and fgsea respectively. TIME deconvolution was quantified using CIBERSORT, an in-silico flow cytometry tool. In aggregate, 42 tumor samples from 19 patients (19 primary tumors with 23 matched metastases) were analyzed. Metastatic sites included lung (n = 6), bone (n = 6), adrenal (n = 4), liver (n = 2), lymph node (n = 2), and soft tissue (n = 3). In unsupervised hierarchical clustering, primary tumors clustered together and not with their matched metastatic tumor. Of the immune cells assayed, primary tumors displayed greater Tregs than their matched (and unmatched) metastases (p < 0.001). Among metastatic sites, bone had high levels of EMT activity compared to their matched primary tumors and lung metastatic tumors were enriched in E2F targets. We demonstrate differences in pathway enrichment and immune cell populations in primary ccRCC and their matched metastases, including a higher infiltration of immunosuppressive T regulatory cells in the tumor immune microenvironment of primary ccRCC. Metastatic tumors not only differed from their paired primary tumors but also differed in gene expression, gene set enrichment, and immune cell composition between metastatic tissue sites.
Insufficient documentation of artificial intelligence (AI) models remains a widespread issue, which hampers reproducibility in research environments and safe integration in clinical departments. Our goal was to develop a standardised, structured, and domain-specific reporting framework tailored to AI models in radiotherapy (RT), enhancing transparency and accountability. A working group was formed after the ESTRO Physics Workshop 2023, "AI for the Fully Automated Radiotherapy Treatment Chain", comprising 16 experts from 13 institutions. We reviewed existing initiatives for AI model and data reporting and drafted an initial template, which was sent for review to all participants. Three popular RT applications were selected to define task-specific fields: synthetic CT, segmentation, and dose prediction. Five review rounds were performed, where suggested changes were voted in a shared online document. Unclear fields and conflicting votes were discussed at online meetings, and consensus was reached by majority voting. The final template included 6 sections: 0) Card metadata, 1) Model basic information; 2) Model technical specifications (i.e. architecture, software and hardware); 3) Training data, methodology, and information; 4) Evaluation data, methodology, and results (a.k.a commissioning for clinical models); and 5) Other considerations, including ethical use, risk analysis, and monitoring. It is publicly available as a downloadable document template and as an interactive web-based form to facilitate information entry. We proposed a practical, consensus-driven template tailored to the unique requirements of AI models in RT, with applicability in both research and clinical environments, conveying the key information required for informed use.
Down syndrome, the most common form of human intellectual disability, results from nondisjunction and an extra copy of chromosome 21 (chr21), also known as trisomy 21 (T21). Small centromeres have been hypothesized to contribute to its etiology, and studies on mice suggest that larger centromeres are more efficiently transmitted, yet complete sequencing of chr21 centromeres has been particularly challenging due to their repetitive nature and homology to chromosome 13. Using long-read sequencing, we sequenced and assembled the centromeres from eight families with a child with T21 (one parent-child trio, six mother-child duos, and one singleton), all resulting from maternal meiosis I errors. A comparison of all proband chr21 centromeres (n = 24) to those of control individuals (n = 287) shows that small centromeres are not enriched in families with T21 (p value = 0.72), contrary to earlier reports. However, chr21 extreme centromere size asymmetry (>10-fold) was observed for two of them. Mothers from these two families with T21 carry some of the smallest chr21 centromeres (143 and 181 kbp) observed in female individuals to date, exhibiting a ∼10.7- and ∼19.4-fold centromeric α-satellite higher-order repeat array size difference between the maternally inherited homologs, respectively. Phylogenetic reconstruction reveals that human chr21 is particularly prone to such asymmetry, with some of the biggest size differences occurring over the last ∼17,000 years of human evolution.
Goal The aim of this official guideline, which was coordinated by the German Society of Gynaecology and Obstetrics (DGGG) together with the German Society of Urology (DGU) and the German Society of Reproductive Medicine (DGRM), is to provide consensus-based recommendations for counselling and the use of fertility preservation measures in prepuscent girls and boys and for patients of reproductive age by evaluating the relevant literature. Methods This S2k guideline was developed by a structured consensus of representative members of various professional associations on behalf of the guideline commission of the DGGG, DGU and DGRM. Recommendations Recommendations for counselling and the use of fertility-preserving measures in patients are presented, taking into account their life circumstances, the planned oncological therapy and the individual risk profile, as well as the procedure for selected tumour entities.
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Pediatric exoskeletons have the potential to aid the walking of children with neuromuscular conditions such as crouch gait. However, current exoskeleton devices often rely on bulky batteries and motors. Recent developments in 3D-printing technologies now allow the construction of lightweight yet stiff parts that are easy to customize and use for pediatric applications. We present the mechanical design of a 3D-printed and spring-powered knee exoskeleton for gait assistance. The device had a mass of ∼1.25 kg per leg and provided a knee extensor moment during the stance phase of gait, simulating the spring-like behavior of the knee. Conversely, the exoskeleton provided no resistance during swing to allow free motion of the joint. To validate the device, we recruited two neurologically intact children to walk on a treadmill with and without the exoskeleton while we recorded kinematics, kinetics, and muscle activity data. Our exoskeleton generated knee extensor moments proportional to its angular excursion and had a peak mean moment of ∼0.1 N·m/kg during stance. Kinetic data showed that subjects decreased their biological knee moment and joint spring-like behavior to compensate for the added exoskeleton moment and stiffness, respectively. We ultimately show that the device is robust and capable of generating extensor moments comparable to devices used to assist the knee in children with crouch gait.
Skeletal muscle blood volume responds to the metabolic demands of exercise and augmented microvasculature reactivity. We sought to explore the effects of exercise intensity (maximal vs. submaximal) on near-infrared spectroscopy (NIRS)-derived blood volume and microvascular reactivity in the acute post-exercise timeframe. Healthy individuals (N = 18) between 18 and 35 years completed a vascular occlusion test (VOT) followed by a maximal cycling test. A second VOT was performed 15-min post-exercise. One week later, the protocol was repeated before and after a submaximal bout of cycling (60% VO2 peak). NIRS was used to assess total hemoglobin (tHb) (i.e., blood volume) before, during, and after exercise, as well as muscle oxygen consumption (mVO2) and microvascular reactivity (StO2% s-1) pre- and post-exercise. Compared with pre-exercise, tHb was elevated at the end of exercise (p < 0.001) and remained elevated 15-min post-exercise (p < 0.001) regardless of trial (combined means pre: 5.39 ± 0.82, during: 14.01 ± 1.73, and post-exercise: 10.89 ± 1.24 O.D.). mVO2 was greater post-exercise in the max vs. submax trial (- 0.36 ± 0.12 vs. - 0.22 ± 0.11% s-1; p < 0.001). Compared with pre-exercise, microvascular reactivity was unchanged following the max trial (1.91 ± 0.61 vs. 1.71 ± 0.61% s-1; p = 0.079) but was greater following the submax trial (1.72 ± 0.43 vs. 1.98 ± 0.59; p = 0.007). Cycling at a submaximal, but not maximal, intensity results in augmented post-exercise microvascular reactivity, while post-exercise increases in skeletal muscle blood volume were found regardless of exercise intensity.
Long-read sequencing improves sensitivity to discover variation in complex repetitive regions, assign parent-of-origin, and distinguish germline from postzygotic mutations. We applied Illumina, Oxford Nanopore Technologies, and PacBio sequencing to discover and validate de novo mutations in 73 children from 42 autism families (157 individuals). We assay 2.77 Gbp of the human genome, yielding on average 95 de novo mutations per transmission (87.5 single-nucleotide substitutions, 7.8 indels), with no significant difference in mutation rate or profile between probands and their unaffected siblings. Long reads increase de novo mutation discovery by 20-40% and double the mutations classified as early embryonic. The germline mutation rate is 1.30×10-8 substitutions/base pair/generation; the postzygotic rate is 0.23×10-8. These rates are significantly increased in repetitive DNA, where segmental duplication mutability is dependent on length and percent identity. Here, we show that enrichment in repeats occurs predominantly postzygotically, likely resulting from faulty DNA repair and interlocus gene conversion.