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Throughout an individual’s lifetime, genomic alterations accumulate in somatic cells1–11. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome12–14, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.

Highly siderophile elements (HSEs), including Re and Os, are used extensively as geochemical tracers and geochronometers to investigate the formation and evolution of Earth’s crust and mantle. Mantle rocks are commonly serpentinized, but the effect of serpentinization on the distribution of HSEs is controversial because HSEs are commonly hosted by rare, micrometer- to sub-micrometer-scale grains of platinum group minerals (PGMs) of ambiguous origin that are challenging to identify, characterize, and interpret. In this study, atom probe tomography (APT) is used to characterize two spatially close PGM grains hosted by a partially serpentinized harzburgite from Macquarie Island, Australia. The APT data reveal an extraordinary level of detail that provides insights into the origin of a complex Cu–Pt alloy grain (average composition ~Cu4Pt). The grain hosts Fe-, Ni-, and Pt-rich sub-grains associated with Rh, variably overlapping networks of Pd- and Cd-enrichment, and OH-rich volumes identified as fluid inclusions. Osmium and Ru are hosted by an idioblastic laurite (RuS2) grain. Compositional, textural, and phase-diagram constraints are consistent with a modified pre-serpentinization origin for the PGMs, and a comparison between observed and calculated grain distributions indicate that while Os isotope ratios were probably unaffected by serpentinization, whole-rock and grain-scale HSE and isotopic ratios may have been decoupled during serpentinization.

ObjectiveTriphenyl phosphate (TPHP) is one of the most commonly used organophosphorus flame retardants that may accumulate in the environment. However, its effects on human reproductive organs have not been well studied. We aimed to investigate the in vitro effects of TPHP in human Ishikawa endometrial cancer cells to elucidate how TPHP exposure disrupts intracellular signaling and cell proliferation in reproductive tissues.MethodsHuman Ishikawa endometrial cancer cells were exposed to TPHP.ResultsExposure to TPHP elevated the levels of estrogen receptor (ER) α and progesterone receptor-B and reduced ER β in human Ishikawa endometrial cancer cells. TPHP stimulated phosphoinositide 3-kinase/protein kinase B and mitogenactivated protein kinase/ extracellular signal-regulated kinases 1/2 kinase signaling, which may contribute to the activation of ER function and induce nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in human Ishikawa endometrial cancer cells. Activated ER and NF-κB stimulate the expression of cyclin D1/ cyclin-dependent kinase (CDK) 4/CDK6, indicating cell cycle progression and proliferation.ConclusionThis report may provide new information on the molecular mechanisms underlying how TPHP exposure dysregulates the cellular physiology of the human endometrium.

With the increasing number of sequencing projects involving families, quality control tools optimized for family genome sequencing are needed. However, accurately quantifying contamination in a DNA mixture is particularly difficult when genetically related family members are the sources. We developed TrioMix, a maximum likelihood estimation (MLE) framework based on Mendel's law of inheritance, to quantify DNA mixture between family members in genome sequencing data of parent–offspring trios. TrioMix can accurately deconvolute any intrafamilial DNA contamination, including parent–offspring, sibling–sibling, parent–parent, and even multiple familial sources. In addition, TrioMix can be applied to detect genomic abnormalities that deviate from Mendelian inheritance patterns, such as uniparental disomy (UPD) and chimerism. A genome-wide depth and variant allele frequency plot generated by TrioMix facilitates tracing the origin of Mendelian inheritance deviations. We showed that TrioMix could accurately deconvolute genomes in both simulated and real data sets.

We report detailed mineralogy and geochemistry of hydrothermal mounds and chimneys in the TA25 West vent field (TA25 WVF), a newly discovered magmatic–hydrothermal system in the Tonga (Tofua) arc. Chimney samples are classified as sulfate- or sulfide-rich, based on major sulfide, sulfosalt, and sulfate minerals. The former type represents a simple mineral assemblage of predominance of anhydrite/gypsum + barite + pyrite, whereas the sulfide-rich chimneys show three different stages of mineralization with decreasing fluid temperature: sphalerite–pyrite dominated stage I, sphalerite–sulfosalts dominated stage II, and stage III is dominated by seawater alteration. Mound samples are characterized by sulfide assemblages and paragenesis similar to those of sulfide-rich samples, but abundant chalcopyrite indicates a relatively high-temperature mineralization. The chimney and mound samples are enriched in Au (average 9.2 ppm), Ag (297 ppm), As (1897 ppm), Sb (689 ppm), Hg (157 ppm), and Se (34.6 ppm). LA–ICP–MS and FE–TEM studies indicate that most of these elements occur in sulfides or sulfosalts in solid solution, although some occur as nanoparticles. This is mainly controlled by the combined effects of fluid conditions (temperature and redox state) and influx of ambient seawater. Petrography and trace-element compositions of sulfides and/or sulfosalts suggest that most concentrations of Au and Ag in the TA25 WVF result from the precipitation and/or adsorption of Au–Ag-bearing nanoparticles on rapidly crystallized sulfides, the substitution of Au and Ag in sulfide and/or sulfosalt minerals, and the saturation of Ag in hydrothermal fluids during late, relatively low-temperature mineralization (34S values (2.1 to 4.3‰) of sulfide minerals relative to the host rocks, and the distribution of CO2-rich hydrothermal plumes (500 to 1000 ppm) suggest that the TA25 WVF is a submarine hydrothermal system influenced by a magmatic contribution in an arc setting. Our results indicate that the magmatic contribution is most likely to play an important role in supplying various metals, including Au and Ag, to the TA25 WVF. Subsequently, the rapid crystallization of sulfides induced by abundant fluid-seawater mixing significantly contributes to the precipitation of Au–Ag-rich mineralization.

Objective: Brain somatic mutations in mTOR pathway genes are a major genetic etiology of focal cortical dysplasia type II (FCDII). Despite a greater ability to detect low-level somatic mutations in the brain by deep sequencing and analytics, about 40% of cases remain genetically unexplained. Methods: We included 2 independent cohorts consisting of 21 patients with mutation-negative FCDII without apparent mutations on conventional deep sequencing of bulk brain. To find ultra-low level somatic variants or structural variants, we isolated cells exhibiting phosphorylation of the S6 ribosomal protein (p-S6) in frozen brain tissues using fluorescence-activated cell sorting (FACS). We then performed deep whole-genome sequencing (WGS; >90×) in p-S6 + cells in a cohort of 11 patients with mutation-negative. Then, we simplified the method to whole-genome amplification and target gene sequencing of p-S6 + cells in independent cohort of 10 patients with mutation-negative followed by low-read depth WGS (10×). Results: We found that 28.6% (6 of 21) of mutation-negative FCDII carries ultra-low level somatic mutations (less than 0.2% of variant allele frequency [VAF]) in mTOR pathway genes. Our method showed ~34 times increase of the average mutational burden in FACS mediated enrichment of p-S6 + cells (average VAF = 5.84%) than in bulky brain tissues (average VAF = 0.17%). We found that 19% (4 of 21) carried germline structural variations in GATOR1 complex undetectable in whole exome or targeted gene sequencing. Conclusions: Our method facilitates the detection of ultra-low level somatic mutations, in specifically p-S6 + cells, and germline structural variations and increases the genetic diagnostic rate up to ~80% for the entire FCDII cohort. ANN NEUROL 2023;93:1082–1093.

We studied the atomic layer deposition (ALD) of titanium oxide (TiO2) thin films using a newly developed heteroleptic titanium precursor with a linked ligand.

As per the fire statistics survey of 2019, 56.5% (152 cases) of the entire fire accidents (269 cases) caused by heating cables were due to electrical factors. Therefore, in the present work, the electrical factors responsible for heating cable fire have been analyzed, and fire prevention measures have been demonstrated through related reproduction experiments. According to heating cable fire statistics, the fire in anti-freezing appliances (heating cables), except for fires caused by electric cable arcing and other unknown factors, can be classified into four types based on installation configurations. These configurations have been classified and tested according to the Technical Regulations for Electrical and Telecommunications Products and Components (K 10013). The results of a comparative experiment on anti-freezing appliances (heating cable) revealed that the configuration “a type of water pipe with a heating cable wrapped around the water pipe and insulation on the outside” showed the highest temperature among the four installation arrangements. Additionally, the maximum difference between the test temperature (K 10013) and the actual temperature was 40 ℃.

Myeloid sarcoma (MS) is an extramedullary tumor that consists of myeloblasts and rarely involves the female reproductive organs. Intestinal Behçet's disease (BD) is a chronic, inflammatory illness that is often associated with myelodysplastic syndrome (MDS). When MDS is diagnosed, some patients with intestinal BD experience synchronous gastrointestinal flares.We report the case of a 49-year-old woman who presented with vaginal bleeding and an incidentally identified MS in the uterine cervix. Subsequent bone marrow biopsy showed simultaneous MDS without chromosomal abnormalities. This is the first reported case of concomitant MS, myelodysplastic disease, and intestinal BD.The accurate diagnosis of MSs that develop at non-predominant sites is crucial for a positive patient prognosis. MDS should be suspected in patients with a history of intestinal BD diagnosed with MS.

Cellular dynamics and fate decision in early human embryogenesis remain largely unknown owing to the challenges of performing studies in human embryos1. Here, we explored whole-genomes of 334 single-cell colonies and targeted deep sequences of 379 bulk tissues obtained from various anatomical locations of seven recently deceased adult human donors. Using somatic mutations as an intrinsic barcode, we reconstructed early cellular phylogenies that demonstrate (1) an endogenous mutational rate that is higher in the first cell division but decreases to approximately one per cell per cell division later in life; (2) universal unequal contribution of early cells to embryo proper, resulting from early cellular bottlenecks that stochastically set aside epiblast cells within the embryo; (3) examples of varying degrees of early clonal imbalances between tissues on the left and right sides of the body, different germ layers and specific anatomical parts and organs; (4) emergence of a few ancestral cells that will substantially contribute to adult cell pools in blood and liver; and (5) presence of mitochondrial DNA heteroplasmy in the fertilized egg. Our approach also provides insights into the age-related mutational processes and loss of sex chromosomes in normal somatic cells. In sum, this study provides a foundation for future studies to complete cellular phylogenies in human embryogenesis. Adult human tissues from diverse sites around the body are used to reconstruct cellular phylogenies from early development, using somatic mutations as an internal barcode.

Synaptic excitation (E) and inhibition (I) stay relatively proportional to each other over different spatiotemporal scales, orchestrating neuronal activity in the brain. This proportionality, referred to as E-I balance, is thought to be critical for neuronal functions because its disruption was observed in many neurological disorders. However, the causal evidence demonstrating its significance is scarce. Here we show that deleting Neuroligin-2 (Nlgn2), a postsynaptic adhesion molecule at inhibitory synapses, from mouse glutamatergic or GABAergic neurons reduces inhibition cell-autonomously without affecting excitation, thereby disrupting E-I balance and causing lethality. In contrast, deleting Nlgn2 constitutively or simultaneously from both glutamatergic and GABAergic neurons results in viable mice. A neural network model shows that reducing inhibition in either neuronal type is detrimental to network activity, but in both types partially re-establishes E-I balance and activity. Together, our results provide evidence for an essential role of E-I balance in brain functions and organism survival.

Porphyry deposits are large, low-grade metal ore bodies that are formed from hydrothermal fluids derived from an underlying magma reservoir. They are important as major sources of critical metals for industry and society, such as copper and gold. However, the magmatic and redox processes required to form economic-grade porphyry deposits remain poorly understood. In this Review, we discuss advances in understanding crustal magmatic conditions that favour the formation of porphyry Cu deposits at subduction zones. Chalcophile metal fertility of mantle-derived arc magmas is primarily modulated by the amount and nature of residual sulfide phases in the mantle wedge during partial melting. Crustal thickness influences the longevity of lower crustal magma reservoirs and the sulfide saturation history. For example, in thick crust, prolonged magma activity with hydrous and oxidized evolving magmas increases ore potential, whereas thin crust favours high chalcophile element fertility, owing to late sulfide saturation. A shallow depth (

We disclose herein a directing group-assisted nickel-catalyzed intermolecular C(sp3)–H amidation using organic azides as nitrene precursors. With the installation of an electronically tailored dire...

SummaryOver the course of an individual’s lifetime, genomic alterations accumulate in somatic cells. However, the mutational landscape by retrotranspositions of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome, is poorly understood in normal cells. Here, we explored the whole-genome sequences of 892 single-cell clones established from various tissues collected from 28 individuals. Remarkably, 88% of colorectal epithelial cells acquired somatic L1 retrotranspositions (soL1Rs), carrying ∼3 events per cell on average with substantial intra- and inter-individual variances, which was accelerated at least 10-fold during tumourigenesis. Breakpoints of soL1Rs suggested that a few variant mechanisms can be involved in the L1 retrotransposition processes. Fingerprinting of donor L1s using source-specific unique sequences revealed 34 hot L1s, 44% of which were newly discovered in this study, and many ultra-rare hot L1s in the human population showed higher retrotransposition potential in somatic lineages than common sources. Multi-dimensional analysis of soL1Rs with early embryonic developmental relationships, genome-wide methylation, and gene expression profiles of the clones demonstrated that (1) soL1Rs occur from early embryogenesis at a substantial rate, (2) epigenetic activation of hot L1s is stochastically acquired during the wave of early global epigenomic reprogramming, rather than by the sporadic loss-of-methylation at the late stage, and (3) most L1 transcripts in the cytoplasm do not generate soL1Rs in somatic lineages. In summary, this study provides insights into the retrotransposition dynamics of L1s in the human genome and the resultant somatic mosaicism in normal human cells.

We describe a protocol for cobalt-catalyzed hydrosilylation of 3-alkynes with accompanying π-bond migration. Mechanistic studies indicate that (i) cobalt(I)-hydride bearing a bulky bisphosphine lig...

The Coronavirus disease-19 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus -2 (SARS-CoV-2), has impacted human lives in the most profound ways with millions of infections and deaths. Scientists and pharmaceutical companies have been in race to produce vaccines against SARS-CoV-2. Vaccine generation usually demands years of developing and testing for efficacy and safety. However, it only took less than one year to generate two mRNA vaccines from their development to deployment. The rapid production time, cost-effectiveness, versatility in vaccine design, and clinically proven ability to induce cellular and humoral immune response have crowned mRNA vaccines with spotlights as most promising vaccine candidates in the fight against the pandemic. In this review, we discuss the general principles of mRNA vaccine design and working mechanisms of the vaccines, and provide an up-to-date summary of pre-clinical and clinical trials on seven anti-COVID-19 mRNA candidate vaccines, with the focus on the two mRNA vaccines already licensed for vaccination. In addition, we highlight the key strategies in designing mRNA vaccines to maximize the expression of immunogens and avoid intrinsic innate immune response. We also provide some perspective for future vaccine development against COVID-19 and other pathogens.