Endogenous retrovirus HERVH-derived lncRNA UCA1 controls human trophoblast development.

Endogenous retroviruses (ERVs) are frequently reactivated in mammalian placenta. It has been proposed that ERVs contribute to shaping the gene regulatory network of mammalian trophoblasts, dominantly acting as species- and placental-specific enhancers. However, whether and how ERVs control human trophoblast development through alternative pathways remains poorly understood. Besides the well-recognized function of human endogenous retrovirus-H (HERVH) in maintaining pluripotency of early human epiblast, here we present a unique role of HERVH on trophoblast lineage development. We found that the LTR7C/HERVH subfamily exhibits an accessible chromatin state in the human trophoblast lineage. Particularly, the LTR7C/HERVH-derived Urothelial Cancer Associated 1 (UCA1), a primate-specific long non-coding RNA (lncRNA), is transcribed in human trophoblasts and promotes the proliferation of human trophoblast stem cells (hTSCs), whereas its ectopic expression compromises human trophoblast syncytialization coinciding with increased interferon signaling pathway. Importantly, UCA1 upregulation is detectable in placental samples from early-onset preeclampsia (EO-PE) patients and the transcriptome of EO-PE placenta exhibits considerable similarities to that of the syncytiotrophoblasts differentiated from UCA1-overexpressing hTSCs, supporting up-regulated UCA1 as a potential biomarker of this disease. Altogether, our data shed light on the versatile regulatory role of HERVH in early human development and provide a unique mechanism whereby ERVs exert a function in human placentation and placental syndromes.

Two-dimensional Cu Plates with Steady Fluid Fields for High-rate Nitrate Electroreduction to Ammonia and Efficient Zn-Nitrate Batteries.

Nitrate electroreduction reaction (eNO3 -RR) to ammonia (NH3) provides a promising strategy for nitrogen utilization, while achieving high selectivity and durability at an industrial scale has remained challenging. Herein, we demonstrated that the performance of eNO3 -RR could be significantly boosted by introducing two-dimensional Cu plates as electrocatalysts and eliminating the general carrier gas to construct a steady fluid field. The developed eNO3 -RR setup provided superior NH3 Faradaic efficiency (FE) of 99 %, exceptional long-term electrolysis for 120 h at 200 mA cm-2, and a record-high yield rate of 3.14 mmol cm-2 h-1. Furthermore, the proposed strategy was successfully extended to the Zn-nitrate battery system, providing a power density of 12.09 mW cm-2 and NH3 FE of 85.4 %, outperforming the state-of-the-art eNO3 -RR catalysts. Coupled with the COMSOL multiphysics simulations and in situ infrared spectroscopy, the main contributor for the high-efficiency NH3 production could be the steady fluid field to timely rejuvenate the electrocatalyst surface during the electrocatalysis.

External Field-Responsive Ternary Non-Noble Metal Oxygen Electrocatalyst for Rechargeable Zinc-Air Batteries.

Despite the increasing effort in advancing oxygen electrocatalysts for zinc-air batteries (ZABs), the performance development gradually reaches a plateau via only ameliorating the electrocatalyst materials. Herein, a new class of external field-responsive electrocatalyst comprising Ni0.5 Mn0.5 Fe2 O4 stably dispersed on N-doped Ketjenblack (Ni0.5 Mn0.5 Fe2 O4 /N-KB) is developed via polymer-assisted strategy for practical ZABs. Briefly, the activity indicator ΔE is significantly decreased to 0.618 V upon photothermal assistance, far exceeding most reported electrocatalysts (generally >0.680 V). As a result, the photothermal electrocatalyst possesses comprehensive merits of excellent power density (319 mW cm-2 ), ultralong lifespan (5163 cycles at 25 mA cm-2 ), and outstanding rate performance (100 mA cm-2 ) for liquid ZABs, and superb temperature and deformation adaptability for flexible ZABs. Such improvement is attributed to the photothermal-heating-enabled synergy of promoted electrical conductivity, reactant-molecule motion, active area, and surface reconstruction, as revealed by operando Raman and simulation. The findings open vast possibilities toward more-energy-efficient energy applications.

NEIL3 promotes cell proliferation of ccRCC via the cyclin D1-Rb-E2F1 feedback loop regulation.

Nei endonuclease VIII-like 3 (NEIL3), a novel tumor-related gene, is differentially expressed and involved in pathophysiological processes in multiple tumors. However, the potential biological functions and molecular mechanisms of NEIL3 in human clear cell renal cell carcinoma (ccRCC) have not been identified. In this research, we demonstrated that NEIL3, transcriptionally activated by E2F1, served as an oncogene to facilitate cell proliferation and cell cycle progression and contribute to tumorigenesis via the cyclin D1-Rb-E2F1 feedback loop in ccRCC. First, we found that NEIL3 expression was upregulated in ccRCC tissues and cell lines compared with matched adjacent nontumor tissues and renal tubular epithelial cells and was also positively correlated with adverse clinicopathological characteristics, such as advanced cancer stages and higher tumor grades, and acted as an independent prognostic marker in ccRCC. Mechanistically, we demonstrated that NEIL3 promoted cell proliferation, DNA replication and cell cycle progression in vitro and tumor growth in vivo. Furthermore, we found that NEIL3 overexpression activated the cyclin D1-Rb-E2F1 pathway, and the E2F1 upregulation transcriptionally activated NEIL3 expression, thus forming a feedback loop. In addition, there was a positive correlation between NEIL3 and E2F1 expression in clinical specimens of ccRCC. Taken together, our results suggest that NEIL3 serves as a proto-oncogene in ccRCC and presents as a novel candidate for ccRCC diagnosis and treatment.

Honeycomb-Structured MoSe2 /rGO Composites as High-Performance Anode Materials for Sodium-Ion Batteries.

Sodium-ion batteries are a promising substitute for lithium batteries due to the abundant resources and low cost of sodium. Herein, honeycomb-shaped MoSe2 /reduced graphene oxide (rGO) composite materials are synthesized from graphene oxide (GO) and MoSe2 through a one-step solvothermal process. Experiments show that the 3D honeycomb structure provides excellent electrolyte penetration while alleviating the volume change during electrochemical cycling. An anode prepared with MoSe2 /rGO composites exhibits significantly improved sodium-ion storage properties, where a large reversible capacity of 215 mAh g-1 is obtained after 2700 cycles at the current density of 30.0 A g-1 or after 5900 cycles at 8.0 A g-1 . When such an anode is paired with Na3 V2 (PO4 )3 to form a full cell, a reversible specific capacity of 107.5 mAh g-1 can be retained after 1000 cycles at the current of 1.0 A g-1 . Transmission electron microscopy, X-ray photoelectron spectroscopy and in situ X-ray diffraction (XRD) characterization reveal the reversible storage reaction of Na ions in the MoSe2 /rGO composites. The significantly enhanced sodium storage capacity is attributed to the unique honeycomb microstructure and the use of ether-based electrolytes. This study illustrates that combining rGO with ether-based electrolytes has tremendous potential in constructing high-performance sodium-ion batteries.

Recent Progress Toward Electrocatalytic Conversion of Nitrobenzene.

Despite that extensive efforts have been dedicated to the search for advanced catalysts to boost the electrocatalytic nitrobenzene reduction reaction (eNBRR), its progress is severely hampered by the limited understanding of the relationship between catalyst structure and its catalytic performance. Herein, this review aims to bridge such a gap by first analyzing the eNBRR pathway to present the main influential factors, such as electrolyte feature, applied potential, and catalyst structure. Then, the recent advancements in catalyst design for eNBRR are comprehensively summarized, particularly about the impacts of chemical composition, morphology, and crystal facets on regulating the local microenvironment, electron and mass transport for boosting catalytic performance. Finally, the future research of eNBRR is also proposed from the perspectives of performance enhancement, expansion of product scope, in-depth understanding of the reaction mechanism, and acceleration of the industrialization process through the integration of upstream and downstream technologies.

Electrocatalytic CO2 Reduction to Ethylene: From Advanced Catalyst Design to Industrial Applications.

The value-added chemicals, monoxide, methane, ethylene, ethanol, ethane, and so on, can be efficiently generated through the electrochemical CO2 reduction reaction (eCO2 RR) when equipped with suitable catalysts. Among them, ethylene is particularly important as a chemical feedstock for petrochemical manufacture. However, despite its high Faradaic efficiency achievable at relatively low current densities, the substantial enhancement of ethylene selectivity and stability at industrial current densities poses a formidable challenge. To facilitate the industrial implementation of eCO2 RR for ethylene production, it is imperative to identify key strategies and potential solutions through comprehending the recent advancements, remaining challenges, and future directions. Herein, the latest and innovative catalyst design strategies of eCO2 RR to ethylene are summarized and discussed, starting with the properties of catalysts such as morphology, crystalline, oxidation state, defect, composition, and surface engineering. The review subsequently outlines the related important state-of-the-art technologies that are essential in driving forward eCO2 RR to ethylene into practical applications, such as CO2 capture, product separation, and downstream reactions. Finally, a greenhouse model that integrates CO2 capture, conversion, storage, and utilization is proposed to present an ideal perspective direction of eCO2 RR to ethylene.

Endogenous retroviruses in development and health.

Endogenous retroviruses (ERVs) are evolutionary remnants of retroviral infections in which the viral genome became embedded as a dormant regulatory element within the host germline. When ERVs become activated, they comprehensively rewire genomic regulatory networks of the host and facilitate critical developmental events, such as preimplantation development and placentation, in a manner specific to species, developmental stage, and tissues. However, accumulating evidence suggests that aberrant ERV transcription compromises genome stability and has been implicated in cellular senescence and various pathogenic processes, underscoring the significance of host genomic surveillance mechanisms. Here, we revisit the prominent functions of ERVs in early development and highlight their emerging roles in mammalian post-implantation development and organogenesis. We also discuss their implications for aging and pathological processes such as microbial infection, immune response. Furthermore, we discuss recent advances in stem-cell-based models, single-cell omics, and genome editing technologies, which serve as beacons illuminating the versatile nature of ERVs in mammalian development and health.

lhCLIP reveals the in vivo RNA-RNA interactions recognized by hnRNPK.

RNA-RNA interactions play a crucial role in regulating gene expression and various biological processes, but identifying these interactions on a transcriptomic scale remains a challenge. To address this, we have developed a new biochemical technique called pCp-biotin labelled RNA hybrid and ultraviolet crosslinking and immunoprecipitation (lhCLIP) that enables the transcriptome-wide identification of intra- and intermolecular RNA-RNA interactions mediated by a specific RNA-binding protein (RBP). Using lhCLIP, we have uncovered a diverse landscape of intermolecular RNA interactions recognized by hnRNPK in human cells, involving all major classes of noncoding RNAs (ncRNAs) and mRNA. Notably, hnRNPK selectively binds with snRNA U4, U11, and U12, and shapes the secondary structure of these snRNAs, which may impact RNA splicing. Our study demonstrates the potential of lhCLIP as a user-friendly and widely applicable method for discovering RNA-RNA interactions mediated by a particular protein of interest and provides a valuable tool for further investigating the role of RBPs in gene expression and biological processes.

Culture conditions of mouse ESCs impact the tumor appearance in vivo.

Various culture conditions by small molecules have been explored to extend pluripotency of stem cells, but their impacts on cell fate in vivo remain elusive. We systematically compared the effects of various culture conditions on the pluripotency and cell fate in vivo of mouse embryonic stem cells (ESCs) by tetraploid embryo complementation assay. Conventional ESC cultures in serum/LIF-based condition produced complete ESC mice and also the survival to adulthood at the highest rates of all other chemical-based cultures. Moreover, long-term examination of the survived ESC mice demonstrated that conventional ESC cultures did not lead to visible abnormality for up to 1.5-2 years, whereas the prolonged chemical-based cultures developed retroperitoneal atypical teratomas or leiomyomas. The chemical-based cultures exhibited transcriptomes and epigenomes that typically differed from those of conventional ESC cultures. Our results warrant further refinement of culture conditions in promoting the pluripotency and safety of ESCs in future applications.

PARP12 regulates mouse oocyte meiotic maturation.

Poly(ADP-ribosyl)ation (PARylation) is an important post-translational modification of proteins that involves the transfer of ADP-ribose moieties, and plays important roles in many biological processes including DNA repair, gene expression, RNA processing, ribosome biogenesis, and protein translation. Though it is accepted that PARylation is crucial for oocyte maturation, little is known about how Mono(ADP-ribosyl)ation (MARylation) regulates this process. Here, we report that Parp12, a mon(ADP-ribosyl) transferase of poly(ADP-ribosyl) polymerase (PARP) family, was highly expressed at all stages of oocytes during meiotic maturation. At germinal vesicle (GV) stage, PARP12 was mainly distributed in cytoplasm. Interestingly, PARP12 formed granular aggregation near to spindle poles during metaphase I (MI) and metaphase II (MII). PARP12 depletion results in abnormal spindle organization and chromosome misalignment in mouse oocytes. Chromosome aneuploidy frequency in PARP12 knockdown oocytes was significantly increased. Importantly, PARP12 knockdown triggers activation of spindle assembly checkpoint as shown by active BUBR1 in PARP12-KD MI oocytes. Besides, F actin was significantly attenuated in PARP12-KD MI oocytes which may affect the asymmetric division process. Transcriptomic analysis demonstrated that PARP12 depletion disrupts transcriptome homeostasis. Collectively, our results showed that the maternally expressed mono(ADPribosyl) transferases PARP12 was essential for oocyte meiotic maturation in mouse.

A new human embryonic cell type associated with activity of young transposable elements allows definition of the inner cell mass.

There remains much that we do not understand about the earliest stages of human development. On a gross level, there is evidence for apoptosis, but the nature of the affected cell types is unknown. Perhaps most importantly, the inner cell mass (ICM), from which the foetus is derived and hence of interest in reproductive health and regenerative medicine, has proven hard to define. Here, we provide a multi-method analysis of the early human embryo to resolve these issues. Single-cell analysis (on multiple independent datasets), supported by embryo visualisation, uncovers a common previously uncharacterised class of cells lacking commitment markers that segregates after embryonic gene activation (EGA) and shortly after undergo apoptosis. The discovery of this cell type allows us to clearly define their viable ontogenetic sisters, these being the cells of the ICM. While ICM is characterised by the activity of an Old non-transposing endogenous retrovirus (HERVH) that acts to suppress Young transposable elements, the new cell type, by contrast, expresses transpositionally competent Young elements and DNA-damage response genes. As the Young elements are RetroElements and the cells are excluded from the developmental process, we dub these REject cells. With these and ICM being characterised by differential mobile element activities, the human embryo may be a "selection arena" in which one group of cells selectively die, while other less damaged cells persist.

Development of a next-generation endogenous OCT4 inducer and its anti-aging effect in vivo.

The identification of small molecules capable of replacing transcription factors has been a longstanding challenge in the generation of human chemically induced pluripotent stem cells (iPSCs). Recent studies have shown that ectopic expression of OCT4, one of the master pluripotency regulators, compromised the developmental potential of resulting iPSCs, This highlights the importance of finding endogenous OCT4 inducers for the generation of clinical-grade human iPSCs. Through a cell-based high throughput screen, we have discovered several new OCT4-inducing compounds (O4Is). In this work, we prepared metabolically stable analogues, including O4I4, which activate endogenous OCT4 and associated signaling pathways in various cell lines. By combining these with a transcription factor cocktail consisting of SOX2, KLF4, MYC, and LIN28 (referred to as "CSKML") we achieved to reprogram human fibroblasts into a stable and authentic pluripotent state without the need for exogenous OCT4. In Caenorhabditis elegans and Drosophila, O4I4 extends lifespan, suggesting the potential application of OCT4-inducing compounds in regenerative medicine and rejuvenation therapy.

HMGXB4 Targets Sleeping Beauty Transposition to Germinal Stem Cells.

Transposons are parasitic genetic elements that frequently hijack vital cellular processes of their host. HMGXB4 is a known Wnt signaling-regulating HMG-box protein, previously identified as a host-encoded factor of Sleeping Beauty (SB) transposition. Here, we show that HMGXB4 is predominantly maternally expressed, and marks both germinal progenitor and somatic stem cells. SB piggybacks HMGXB4 to activate transposase expression and target transposition to germinal stem cells, thereby potentiating heritable transposon insertions. The HMGXB4 promoter is located within an active chromatin domain, offering multiple looping possibilities with neighboring genomic regions. HMGXB4 is activated by ERK2/MAPK1, ELK1 transcription factors, coordinating pluripotency and self-renewal pathways, but suppressed by the KRAB-ZNF/TRIM28 epigenetic repression machinery, also known to regulate transposable elements. At the post-translational level, SUMOylation regulates HMGXB4, which modulates binding affinity to its protein interaction partners and controls its transcriptional activator function via nucleolar compartmentalization. When expressed, HMGXB4 can participate in nuclear-remodeling protein complexes and transactivate target gene expression in vertebrates. Our study highlights HMGXB4 as an evolutionarily conserved host-encoded factor that assists Tc1/Mariner transposons to target the germline, which was necessary for their fixation and may explain their abundance in vertebrate genomes.

Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity.

The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer (CRC). In this study, we identified reduced microvessel density (MVD) and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance. We focused on the effect of metformin on MVD, vascular maturity, and endothelial apoptosis of CRCs with a non-angiogenic phenotype, and further investigated its effect in overcoming chemoresistance. In situ transplanted cancer models were established to compare MVD, endothelial apoptosis and vascular maturity, and function in tumors from metformin- and vehicle-treated mice. An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis. Transcriptome sequencing was performed for genetic screening. Non-angiogenic CRC developed independently of angiogenesis and was characterized by vascular leakage, immaturity, reduced MVD, and non-hypoxia. This phenomenon had also been observed in human CRC. Furthermore, non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro. By suppressing endothelial apoptosis, metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity. Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling, which was abrogated by metformin administration. These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC. By suppressing endothelial apoptosis, metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.

V2O3@C Microspheres as the High-Performance Cathode Materials for Advanced Aqueous Zinc-Ion Storage.

Vanadium oxides attract increasing research interests for constructing the cathode of aqueous zinc-ion batteries (ZIBs) because of high theoretical capacity, but the low intrinsic conductivity and unstable phase changes during the charge/discharge process pose great challenges for their adoption. In this work, V2O3@C microspheres were developed to achieve enhanced conductivity and improved stability of phase changes. Compounding vanadium oxides and conductive carbon through the in-situ carbonization led to significant improvement of the cathode materials. ZIBs prepared with V2O3@C cathodes produce a specific capacity of 420 mA h g-1 at 0.2 A g-1. A reversible capacity of 132 mA h g-1 was achieved at 21.0 A g-1. After 2000 cycles, the electrode could still deliver a capacity of 202 mA h g-1 at the current of 5.0 A g-1. Besides, the energy density of batteries constructed with the thus-prepared electrodes was about 294 W h kg-1 at 148 W kg-1 power. The in-situ compounding of V2O3 and carbon resulted in a microstructure that facilitated the stable phase transformation of ZnxV2O5-a·nH2O (ZnVOH), which provided more Zn2+ storage activity than the original phase before electrochemical activation. Moreover, the in-situ compositing strategy presents a simple route to the development of ZIB cathodes with promising performance.

HIF-1α inhibitor YC-1 suppresses triple-negative breast cancer growth and angiogenesis by targeting PlGF/VEGFR1-induced macrophage polarization.

Triple negative breast cancer (TNBC) is an invasive and metastatic phenotype of breast cancer with limited treatment options. Published studies have demonstrated an inhibitory effect of HIF-α inhibition by its inhibitor YC-1 (lificiguat) on growth and angiogenesis of TNBC. However, the underlying mechanism remains poorly understood. In the current paper, our results show that HIF-1α inhibitor significantly inhibited TNBC growth by increasing cellular apoptosis and decreasing MVD, independent of a cell-autonomous mechanism in both endothelial and tumor cells. Genetic screening and in vivo experiments showed that a large number of M2-polarized TAMs accumulated in the hypoxic peri-necrotic region (PNR), where placental growth factor (PlGF) and its ligand, vascular endothelial growth factor receptor-1 (VEGFR-1) were upregulated. Furthermore, YC-1 skewed the polarization of TAMs away from M2 to M1 phenotype, therefore inhibiting TNBC angiogenesis and growth. This effect was further abrogated by VEGFR-1 neutralization and TAM depletion following clodronate liposome injection. These findings provide preclinical evidence for an indirect mechanism underlying YC-1-induced suppression of TNBC growth and angiogenesis, thereby offering a treatment option for TNBC.

Metformin enhances T lymphocyte anti-tumor immunity by increasing the infiltration via vessel normalization.

Abnormal tumor vasculature blocks the extravasation of T lymphocytes into the tumor, thereby suppressing anti-tumor immunity. Recently, metformin has been shown to affect tumor vasculature and enhance T lymphocyte anti-tumor immunity. However, whether or how metformin affects T lymphocyte anti-tumor immunity via a vascular mechanism remains poorly understood. Herein, we show that a large number of CD8+ lymphocytes gathered in the peri-tumoral region, while very few infiltrated the tumor. Metformin administration increased the expression of anti-tumor immunity-associated genes and the number of tumor-infiltrating CD8+ lymphocytes. Injection of CD8 but not CD4 neutralization antibody into tumor-bearing mice significantly abrogated the anti-tumor effect of metformin. Critically, CD8+ lymphocytes were found to pass through the wall of perfused vessel. Further results of immunofluorescent staining showed that metformin greatly elevated tumor perfusion, which was accompanied by increased vascular maturity in the intratumoral region (ITR) but not peritumoral region (PTR). These findings provide evidence for the vascular mechanism involved in metformin-induced enhancement of T lymphocyte anti-tumor immunity. By remodeling the abnormal tumor vasculature, also called vessel normalization metformin increases vascular maturity and tumor perfusion, thus allowing more CD8+ lymphocytes to infiltrate the tumor.