Dux activates metabolism-lactylation-MET network during early iPSC reprogramming with Brg1 as the histone lactylation reader.

The process of induced pluripotent stem cells (iPSCs) reprogramming involves several crucial events, including the mesenchymal-epithelial transition (MET), activation of pluripotent genes, metabolic reprogramming, and epigenetic rewiring. Although these events intricately interact and influence each other, the specific element that regulates the reprogramming network remains unclear. Dux, a factor known to promote totipotency during the transition from embryonic stem cells (ESC) to 2C-like ESC (2CLC), has not been extensively studied in the context of iPSC reprogramming. In this study, we demonstrate that the modification of H3K18la induced by Dux overexpression controls the metabolism-H3K18la-MET network, enhancing the efficiency of iPSC reprogramming through a metabolic switch and the recruitment of p300 via its C-terminal domain. Furthermore, our proteomic analysis of H3K18la immunoprecipitation experiment uncovers the specific recruitment of Brg1 during reprogramming, with both H3K18la and Brg1 being enriched on the promoters of genes associated with pluripotency and epithelial junction. In summary, our study has demonstrated the significant role of Dux-induced H3K18la in the early reprogramming process, highlighting its function as a potent trigger. Additionally, our research has revealed, for the first time, the binding of Brg1 to H3K18la, indicating its role as a reader of histone lactylation.

Stretchable and negative-Poisson-ratio porous metamaterials.

Highly stretchable porous materials are promising for flexible electronics but their fabrication is a great challenge. Herein, several kinds of highly stretchable conductive porous elastomers with low or negative Poisson's ratios are achieved by uniaxial, biaxial, and triaxial hot-pressing strategies. The reduced graphene oxide/polymer nanocomposite elastomers with folded porous structures obtained by uniaxial hot pressing exhibit high stretchability up to 1200% strain. Furthermore, the meta-elastomers with reentrant porous structures combining high biaxial (or triaxial) stretchability and negative Poisson's ratios are achieved by biaxial (or triaxial) hot pressing. The resulting elastomer-based wearable strain sensors exhibit an ultrawide response range (0-1200%). The materials can be applied for smart thermal management and electromagnetic interference shielding, which are achieved by regulating the porous microstructures via stretching. This work provides a versatile strategy to highly stretchable and negative-Poisson-ratio porous materials with promising features for various applications such as flexible electronics, thermal management, electromagnetic shielding, and energy storage.

Adenosylhomocysteinase plays multiple roles in maintaining the identity and pluripotency of mouse embryonic stem cells†.

Adenosylhomocysteinase (AHCY), a key enzyme in the methionine cycle, is essential for the development of embryos and the maintenance of mouse embryonic stem cells (mESCs). However, the precise underlying mechanism of Ahcy in regulating pluripotency remains unclear. As the only enzyme that can hydrolyze S-adenosylhomocysteine in mammals, AHCY plays a critical role in the metabolic homeostasis, epigenetic remodeling, and transcriptional regulation. Here, we identified Ahcy as a direct target of OCT4 and unveiled that AHCY regulates the self-renewal and differentiation potency of mESCs through multiple mechanisms. Our study demonstrated that AHCY is required for the metabolic homeostasis of mESCs. We revealed the dual role of Ahcy in both transcriptional activation and inhibition, which is accomplished via the maintenance of H3K4me3 and H3K27me3, respectively. We found that Ahcy is required for H3K4me3-dependent transcriptional activation in mESCs. We also demonstrated that AHCY interacts with polycomb repressive complex 2 (PRC2), thereby maintaining the pluripotency of mESCs by sustaining the H3K27me3-regulated transcriptional repression of related genes. These results reveal a previously unrecognized OCT4-AHCY-PRC2 axis in the regulation of mESCs' pluripotency and provide insights into the interplay between transcriptional factors, cellular metabolism, chromatin dynamics and pluripotency regulation.

Attributing Atmospheric Phosphorus in the Himalayas: Biomass Burning vs Mineral Dust.

Atmospheric phosphorus is a vital nutrient for ecosystems whose sources and fate are still debated in the fragile Himalayan region, hindering our comprehension of its local ecological impact. This study provides novel insights into atmospheric phosphorus based on the study of total suspended particulate matter at the Qomolangma station. Contrary to the prevailing assumptions, we show that biomass burning (BB), not mineral dust, dominates total dissolved phosphorus (TDP, bioavailable) deposition in this arid region, especially during spring. While total phosphorus is mainly derived from dust (77% annually), TDP is largely affected by the transport of regional biomass-burning plumes from South Asia. During BB pollution episodes, TDP causing springtime TDP fluxes alone accounts for 43% of the annual budget. This suggests that BB outweighs dust in supplying bioavailable phosphorus, a critical nutrient, required to sustain Himalayas' ecological functions. Overall, this first-hand field evidence refines the regional and global phosphorus budget by demonstrating that BB emission, while still unrecognized, is a significant source of P, even in the remote mountains of the Himalayas. It also reveals the heterogeneity of atmospheric phosphorus deposition in that region, which will help predict changes in the impacted ecosystems as the deposition patterns vary.

Highly cooperative chimeric super-SOX induces naive pluripotency across species.

Our understanding of pluripotency remains limited: iPSC generation has only been established for a few model species, pluripotent stem cell lines exhibit inconsistent developmental potential, and germline transmission has only been demonstrated for mice and rats. By swapping structural elements between Sox2 and Sox17, we built a chimeric super-SOX factor, Sox2-17, that enhanced iPSC generation in five tested species: mouse, human, cynomolgus monkey, cow, and pig. A swap of alanine to valine at the interface between Sox2 and Oct4 delivered a gain of function by stabilizing Sox2/Oct4 dimerization on DNA, enabling generation of high-quality OSKM iPSCs capable of supporting the development of healthy all-iPSC mice. Sox2/Oct4 dimerization emerged as the core driver of naive pluripotency with its levels diminished upon priming. Transient overexpression of the SK cocktail (Sox+Klf4) restored the dimerization and boosted the developmental potential of pluripotent stem cells across species, providing a universal method for naive reset in mammals.

Sulfination of Unactivated Allylic Alcohols via Sulfinate-Sulfone Rearrangement.

A dehydrative cross-coupling of unactivated allylic alcohols with sulfinic acids was achieved under catalyst-free conditions. This reaction proceeded via allyl sulfination and concomitant allyl sulfinate-sulfone rearrangement. Various allylic sulfones could be obtained in good to excellent yields with water as the only byproduct. This study expands the synthetic toolbox for constructing allylic sulfone molecules.

Biomimetic Transparent Layered Tough Aerogels for Thermal Superinsulation and Triboelectric Nanogenerator.

Transparent aerogels are ideal candidates for thermally insulating windows, solar thermal receivers, electronics, etc. However, they are usually prepared via energy-consuming supercritical drying and show brittleness and low tensile strength, significantly restricting their practical applications. It remains a great challenge to prepare transparent aerogels with high tensile strength and toughness. Herein, biomimetic transparent tough cellulose nanofiber-based nanocomposite aerogels with a layered nanofibrous structure are achieved by vacuum-assisted self-assembly combined with ambient pressure drying. The nacre-like layered homogeneous nanoporous structures can reduce light scattering and effectively transfer stress and prevent stress concentration under external forces. The aerogels exhibit an attractive combination of excellent transparency and hydrophobicity, high compressive and tensile strengths, high toughness, excellent machinability, thermal superinsulation, and wide working temperature range (-196 to 230 °C). It is demonstrated that they can be used for superinsulating windows of buildings and high-efficient thermal management for electronics and human bodies. In addition, a prototype of transparent flexible aerogel-based triboelectric nanogenerator is developed. This work provides a promising pathway toward transparent tough porous materials for energy saving/harvesting, thermal management, electronics, sensors, etc.

In vitro generation of mouse morula-like cells.

Generating cells with the molecular and functional properties of embryo cells and with full developmental potential is an aim with fundamental biological significance. Here we report the in vitro generation of mouse transient morula-like cells (MLCs) via the manipulation of signaling pathways. MLCs are molecularly distinct from embryonic stem cells (ESCs) and cluster instead with embryo 8- to 16-cell stage cells. A single MLC can generate a blastoid, and the efficiency increases to 80% when 8-10 MLCs are used. MLCs make embryoids directly, efficiently, and within 4 days. Transcriptomic analysis shows that day 4-5 MLC-derived embryoids contain the cell types found in natural embryos at early gastrulation. Furthermore, MLCs introduced into morulae segregate into epiblast (EPI), primitive endoderm (PrE), and trophectoderm (TE) fates in blastocyst chimeras and have a molecular signature indistinguishable from that of host embryo cells. These findings represent the generation of cells that are molecularly and functionally similar to the precursors of the first three cell lineages of the embryo.

Three-dimensional molecular architecture of mouse organogenesis.

Mammalian embryos exhibit sophisticated cellular patterning that is intricately orchestrated at both molecular and cellular level. It has recently become apparent that cells within the animal body display significant heterogeneity, both in terms of their cellular properties and spatial distributions. However, current spatial transcriptomic profiling either lacks three-dimensional representation or is limited in its ability to capture the complexity of embryonic tissues and organs. Here, we present a spatial transcriptomic atlas of all major organs at embryonic day 13.5 in the mouse embryo, and provide a three-dimensional rendering of molecular regulation for embryonic patterning with stacked sections. By integrating the spatial atlas with corresponding single-cell transcriptomic data, we offer a detailed molecular annotation of the dynamic nature of organ development, spatial cellular interactions, embryonic axes, and divergence of cell fates that underlie mammalian development, which would pave the way for precise organ engineering and stem cell-based regenerative medicine.

Wildfire-Derived Nitrogen Aerosols Threaten the Fragile Ecosystem in Himalayas and Tibetan Plateau.

Himalayas and Tibetan Plateau (HTP) is important for global biodiversity and regional sustainable development. While numerous studies have revealed that the ecosystem in this unique and pristine region is changing, their exact causes are still poorly understood. Here, we present a year-round (23 March 2017 to 19 March 2018) ground- and satellite-based atmospheric observation at the Qomolangma monitoring station (QOMS, 4276 m a.s.l.). Based on a comprehensive chemical and stable isotope (15N) analysis of nitrogen compounds and satellite observations, we provide unequivocal evidence that wildfire emissions in South Asia can come across the Himalayas and threaten the HTP's ecosystem. Such wildfire episodes, mostly occurring in spring (March-April), not only substantially enhanced the aerosol nitrogen concentration but also altered its composition (i.e., rendering it more bioavailable). We estimated a nitrogen deposition flux at QOMS of ∼10 kg N ha-1 yr-1, which is approximately twice the lower value of the critical load range reported for the Alpine ecosystem. Such adverse impact is particularly concerning, given the anticipated increase of wildfire activities in the future under climate change.

Establishing extended pluripotent stem cells from human urine cells.

BACKGROUND: Extended pluripotent stem cells (EPSCs) can contribute to both embryonic and trophectoderm-derived extraembryonic tissues. Therefore, EPSCs have great application significance for both research and industry. However, generating EPSCs from human somatic cells remains inefficient and cumbersome. RESULTS: In this study, we established a novel and robust EPSCs culture medium OCM175 with defined and optimized ingredients. Our OCM175 medium contains optimized concentration of L-selenium-methylcysteine as a source of selenium and ROCK inhibitors to maintain the single cell passaging ability of pluripotent stem cells. We also used Matrigel or the combination of laminin 511 and laminin 521(1:1) to bypass the requirement of feeder cells. With OCM175 medium, we successfully converted integration-free iPSCs from easily available human Urine-Derived Cells (hUC-iPSCs) into EPSCs (O-IPSCs). We showed that our O-IPSCs have the ability to form both intra- and extra- embryonic chimerism, and could contribute to the trophoblast ectoderm lineage and three germ layer cell lineages. CONCLUSIONS: In conclusion, our novel OCM175 culture medium has defined, optimized ingredients, which enables efficient generation of EPSCs in a feeder free manner. With the robust chimeric and differentiation potential, we believe that this system provides a solid basis to improve the application of EPSCs in regenerative medicine.

Organic aerosols in the inland Tibetan Plateau: New insights from molecular tracers.

Aerosols affect the radiative forcing of the global climate and cloud properties. Organic aerosols are among the most important, yet least understood, components of the sensitive Tibetan Plateau atmosphere. Here, the concentration of and the seasonal and diurnal variations in biomass burning and biogenic aerosols, and their contribution to organic aerosols in the inland Tibetan Plateau were investigated using molecular tracers. Biomass burning tracers including levoglucosan and its isomers, and aromatic acids showed higher concentrations during winter than in summer. Molecular tracers of primary and secondary biogenic organic aerosols were more abundant during summer than those in winter. Meteorological conditions were the main factors influencing diurnal variations in most organic molecular tracers during both seasons. According to the tracer-based method, we found that biogenic secondary organic aerosols (38.5 %) and fungal spores (14.4 %) were the two dominant contributors to organic aerosols during summer, whereas biomass burning (15.4 %) was an important aerosol source during winter at remote continental background site. Results from the positive matrix factor source apportionment also demonstrate the importance of biomass burning and biogenic aerosols in the inland Tibetan Plateau. During winter, the long-range transport of biomass burning from South Asia contributes to organic aerosols. In contrast, the precursors, biogenic secondary organic aerosols, and fungal spores from local emissions/long-range transport are the major sources of organic aerosols during summer. Further investigation is required to distinguish between local emissions and the long-range transport of organic aerosols. In-depth insights into the organic aerosols in the Tibetan Plateau are expected to reduce the uncertainties when evaluating aerosol effects on the climate system in the Tibetan Plateau.

Homogeneity of XEN Cells Is Critical for Generation of Chemically Induced Pluripotent Stem Cells.

In induced pluripotent stem cells (iPSCs), pluripotency is induced artificially by introducing the transcription factors Oct4, Sox2, Klf4, and c-Myc. When a transgene is introduced using a viral vector, the transgene may be integrated into the host genome and cause a mutation and cancer. No integration occurs when an episomal vector is used, but this method has a limitation in that remnants of the virus or vector remain in the cell, which limits the use of such iPSCs in therapeutic applications. Chemical reprogramming, which relies on treatment with small-molecule compounds to induce pluripotency, can overcome this problem. In this method, reprogramming is induced according to the gene expression pattern of extra-embryonic endoderm (XEN) cells, which are used as an intermediate stage in pluripotency induction. Therefore, iPSCs can be induced only from established XEN cells. We induced XEN cells using small molecules that modulate a signaling pathway and affect epigenetic modifications, and devised a culture method in which can be produced homogeneous XEN cells. At least 4 passages were required to establish morphologically homogeneous chemically induced XEN (CiXEN) cells, whose properties were similar to those of XEN cells, as revealed through cellular and molecular characterization. Chemically iPSCs derived from CiXEN cells showed characteristics similar to those of mouse embryonic stem cells. Our results show that the homogeneity of CiXEN cells is critical for the efficient induction of pluripotency by chemicals.

Learn to Estimate Genetic Mutation and Microsatellite Instability with Histopathology H&E Slides in Colon Carcinoma.

Colorectal cancer is one of the most common malignancies and the third leading cause of cancer-related mortality worldwide. Identifying KRAS, NRAS, and BRAF mutations and estimating MSI status is closely related to the individualized therapeutic judgment and oncologic prognosis of CRC patients. In this study, we introduce a cascaded network framework with an average voting ensemble strategy to sequentially identify the tumor regions and predict gene mutations & MSI status from whole-slide H&E images. Experiments on a colorectal cancer dataset indicate that the proposed method can achieve higher fidelity in both gene mutation prediction and MSI status estimation. In the testing set, our method achieves 0.792, 0.886, 0.897, and 0.764 AUCs for KRAS, NRAS, BRAF, and MSI, respectively. The results suggest that the deep convolutional networks have the potential to provide diagnostic insight and clinical guidance directly from pathological H&E slides.

Unexpected molecular diversity of brown carbon formed by Maillard-like reactions in aqueous aerosols.

Atmospheric brown carbon (BrC) exerts a key impact on the global radiative balance due to its light-absorbing properties. Maillard-like reactions between carbonyl and amino compounds have been identified as an important pathway for forming secondary BrC. Although optical properties have been widely studied, the molecular composition of secondary BrC generated in Maillard chemistry remains unclear, resulting in a knowledge gap to understand its formation and light-absorbing mechanism. In this study, a combination of optical spectroscopy, 1H nuclear magnetic resonance (NMR), and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was employed to comprehensively characterize the chemical and light-absorbing characteristics of secondary BrC. The results indicate that both the light-absorbing and molecular characteristics of secondary BrC were highly related to the structures of their precursors. Organic amine precursors consistently result in enhanced light-absorbing capacities of BrC compared to ammonium, but have inconsistent effects on the molecular diversity of BrC. Compared to amino precursors (i.e., glycine, ethylamine, propylamine, and ammonium), carbonyl precursors play a more important role in determining the molecular diversity of BrC. Different from black carbon, the light-absorbing products from Maillard-like reactions are mainly nitrogen-containing heterocycles. Unexpectedly, 35-64% of molecular formulae detected in real atmospheric samples were found in simulated Maillard reaction products, implying a potentially important contribution of Maillard chemistry to the atmospheric organic molecular pool. These results will improve our understanding of the formation and molecular diversity of BrC, and further help to manage emissions of secondary aerosol precursors.

Effects of Valence States of Working Cations on the Electrochemical Performance of Sodium Vanadate.

Supercapacitors have received much attention as large-scale energy storage devices for high power density and ultralong cycling life. In this work, sodium vanadate Na0.76V6O15/poly(3,4-ethylenedioxythiophene) (PEDOT) nanocables with deficient bridge oxygen at the interface (denoted Vo••-PNVO) have been tailored for supercapacitors through the in situ polymerization of 3,4-ethylenedioxythiophene and studied using three different electrolytes. Experiments and theoretical calculations reveal that all Na+, Zn2+, and Al3+ ions appear as hydrates in aqueous solutions but insert into the crystal structure as Na+ ions and Zn2+-H2O and Al3+-H2O hydrates, respectively. In comparison with the Zn2+-H2O and Al3+-H2O hydrates, Na+ ions with a smaller radius diffuse more quickly in Vo••-PNVO. Thus, Vo••-PNVO delivers better charge storage capability and stability when an electrolyte with Na+ ions is used. The results strongly suggest that an electrostatic interaction is significant in determining transport properties and storage capacities, rather than hydrate radii or valence states.

Rolling back human pluripotent stem cells to an eight-cell embryo-like stage.

After fertilization, the quiescent zygote experiences a burst of genome activation that initiates a short-lived totipotent state. Understanding the process of totipotency in human cells would have broad applications. However, in contrast to in mice1,2, demonstration of the time of zygotic genome activation or the eight-cell (8C) stage in in vitro cultured human cells has not yet been reported, and the study of embryos is limited by ethical and practical considerations. Here we describe a transgene-free, rapid and controllable method for producing 8C-like cells (8CLCs) from human pluripotent stem cells. Single-cell analysis identified key molecular events and gene networks associated with this conversion. Loss-of-function experiments identified fundamental roles for DPPA3, a master regulator of DNA methylation in oocytes3, and TPRX1, a eutherian totipotent cell homeobox (ETCHbox) family transcription factor that is absent in mice4. DPPA3 induces DNA demethylation throughout the 8CLC conversion process, whereas TPRX1 is a key executor of 8CLC gene networks. We further demonstrate that 8CLCs can produce embryonic and extraembryonic lineages in vitro or in vivo in the form of blastoids5 and complex teratomas. Our approach provides a resource to uncover the molecular process of early human embryogenesis.

A balanced Oct4 interactome is crucial for maintaining pluripotency.

Oct4 collaborates primarily with other transcriptional factors or coregulators to maintain pluripotency. However, how Oct4 exerts its function is still unclear. Here, we show that the Oct4 linker interface mediates competing yet balanced Oct4 protein interactions that are crucial for maintaining pluripotency. Oct4 linker mutant embryonic stem cells (ESCs) show decreased expression of self-renewal genes and increased expression of differentiation genes, resulting in impaired ESC self-renewal and early embryonic development. The linker mutation interrupts the balanced Oct4 interactome. In mutant ESCs, the interaction between Oct4 and Klf5 is decreased. In contrast, interactions between Oct4 and Cbx1, Ctr9, and Cdc73 are increased, disrupting the epigenetic state of ESCs. Control of the expression level of Klf5, Cbx1, or Cdc73 rebalances the Oct4 interactome and rescues the pluripotency of linker mutant ESCs, indicating that such factors interact with Oct4 competitively. Thus, we provide previously unidentified molecular insights into how Oct4 maintains pluripotency.

Genome-wide analysis of cell-Free DNA methylation profiling with MeDIP-seq identified potential biomarkers for colorectal cancer.

BACKGROUND: Colorectal cancer is the most common malignancy and the third leading cause of cancer-related death worldwide. This study aimed to identify potential diagnostic biomarkers for colorectal cancer by genome-wide plasma cell-free DNA (cfDNA) methylation analysis. METHODS: Peripheral blood from colorectal cancer patients and healthy controls was collected for cfDNA extraction. Genome-wide cfDNA methylation profiling, especially differential methylation profiling between colorectal cancer patients and healthy controls, was performed by methylated DNA immunoprecipitation coupled with high-throughput sequencing (MeDIP-seq). Logistic regression models were established, and the accuracy of this diagnostic model for colorectal cancer was verified using tissue-sourced data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) due to the lack of cfDNA methylation data in public datasets. RESULTS: Compared with the control group, 939 differentially methylated regions (DMRs) located in promoter regions were found in colorectal cancer patients; 16 of these DMRs were hypermethylated, and the remaining 923 were hypomethylated. In addition, these hypermethylated genes, mainly PRDM14, RALYL, ELMOD1, and TMEM132E, were validated and confirmed in colorectal cancer by using publicly available DNA methylation data. CONCLUSIONS: MeDIP-seq can be used as an optimal approach for analyzing cfDNA methylomes, and 12 probes of four differentially methylated genes identified by MeDIP-seq (PRDM14, RALYL, ELMOD1, and TMEM132E) could serve as potential biomarkers for clinical application in patients with colorectal cancer.