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Abstract Transposable elements (TEs), once considered genomic “junk”, are now recognized as critical regulators of genome function and human disease. These mobile genetic elements—including retrotransposons (long interspersed nuclear elements [LINE-1], Alu, short interspersed nuclear element-variable numbers of tandem repeats-Alu [SVA], and human endogenous retrovirus [HERV]) and DNA transposons—are tightly regulated by multilayered mechanisms that operate from transcription through to genomic integration. Although typically silenced in somatic cells, TEs are transiently activated during key developmental stages—such as zygotic genome activation and cell fate determination—where they influence chromatin architecture, transcriptional networks, RNA processing, and innate immune responses. Dysregulation of TEs, however, can lead to genomic instability, chronic inflammation, and various pathologies, including cancer, neurodegeneration, and aging. Paradoxically, their reactivation also presents new opportunities for clinical applications, particularly as diagnostic biomarkers and therapeutic targets. Understanding the dual role of TEs—and balancing their contributions to normal development and disease—is essential for advancing novel therapies and precision medicine.

Long interspersed nuclear element-1 (LINE-1 or L1) is a retrotransposon group that constitutes 17% of the human genome and shows variable expression across cell types. However, the control of L1 expression and its function in gene regulation are incompletely understood. Here we show that L1 transcription activates long-range gene expression. Genome-wide CRISPR–Cas9 screening using a reporter driven by the L1 5′ UTR in human cells identifies functionally diverse genes affecting L1 expression. Unexpectedly, altering L1 expression by knockout of regulatory genes impacts distant gene expression. L1s can physically contact their distal target genes, with these interactions becoming stronger upon L1 activation and weaker when L1 is silenced. Remarkably, L1s contact and activate genes essential for zygotic genome activation (ZGA), and L1 knockdown impairs ZGA, leading to developmental arrest in mouse embryos. These results characterize the regulation and function of L1 in long-range gene activation and reveal its importance in mammalian ZGA. A CRISPR–Cas9 screen identifies genes that modulate long interspersed nuclear element-1 (LINE-1) expression in human cells. LINE-1 5′ UTRs have enhancer features and can activate long-range gene expression, including during zygotic genome activation.

Purpose To investigate the different clinical and cytogenetic features of skull base meningiomas (SBMs) and non-SBMs (NSBMs). Methods We conducted a retrospective study on a series of 316 patients with primary intracranial meningiomas. The t-test and the Chi-square test were used to analyze the differences between 194 SBMs and 122 NSBMs. The Cox analysis was used to determine prognostic factors for tumor recurrence. Results Compared with NSBMs, on average, the age of patients with SBMs was about 2.88 years younger (p = 0.024); the duration of operation of SBMs was 2.73 h longer (p < 0.001); the duration of hospital stays of patients with SBMs was about 6.76 days longer (p < 0.001); the tumor volume was 7.69 cm 3 smaller (p = 0.025); the intraoperative blood loss was 147.61ml more (p = 0.039); the total cost of SBMs was 1.39 times more (p < 0.001); the preoperative KPS, postoperative KPS, and follow-up KPS of patients with SBMs were all respectively lower (p < 0.001); Gross total resection was less achieved (p < 0.001). SBMs (average of 20.80 per sample) had a smaller total number of copy number variations (CNVs) than NSBMs (29.98 per sample) (p = 0.009). Extremely large CNVs (> 5 Mb) were more likely to present in NSBMs (p < 0.001). Cox analysis showed that subtotal resection (p = 0.002) and the total number of CNVs (p = 0.015) were independent risk factors for tumor recurrence. Conclusions The clinical and cytogenetic features of SBMs were different from NSBMs. Moreover, the degree of resection and the total number of whole-genome CNVs were independent prognostic factors for tumor recurrence.

Abstract Postzygotic mutations are acquired in all of the normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenesis causing factors. The process and underlying mechanism of postzygotic mutations in normal tissues is still poorly understood. In this study, we investigated postzygotic mutation spectra in healthy individuals by optimized ultra-deep exome sequencing of time series samples from the same volunteer and samples from different individuals. In cells of blood, sperm, and muscle, we resolved three common types of mutational signature. Two of them are known to represent clock-like mutational processes, and their proportions in mutation profiles associated with polymorphisms of epigenetic regulation genes, suggesting the contribution of personal genetic backgrounds to underlying biological process. Notably, the third signature, characterized by C>T transitions at GpCpN sites, tends to be a feature of diverse normal tissues. Mutations of this type were likely to occur early in embryo development even before the tissue differentiation, as indicated by their relatively high allele frequencies, sharing variants between multiple tissues, and lacking of age-related accumulation. Almost all tumors shown in public datasets did not have this signature detected except for 19.6% of clear cell renal cell carcinoma samples, which featured by activation of the hypoxia-induced signaling pathway. Moreover, in vitro activation of HIF signaling pathway successfully introduced the corresponding mutation profile of this signature in a culture-expanded human embryonic stem cell line. Therefore, embryonic hypoxia may explain this novel signature across multiple normal tissues. Our study suggest hypoxic conditions in the early stage of embryo development may be a crucial factor for the C>T transitions at GpCpN sites and individual genetic background also related to shaping human postzygotic mutation profiles. Competing Interest Statement The authors have declared no competing interest. Footnotes * author affiliations updated

Human telomerase is a RNA–protein complex that extends the 3′ end of linear chromosomes by synthesizing multiple copies of the telomeric repeat TTAGGG 1 . Its activity is a determinant of cancer progression, stem cell renewal and cellular aging 2 – 5 . Telomerase is recruited to telomeres and activated for telomere repeat synthesis by the telomere shelterin protein TPP1 6 , 7 . Human telomerase has a bilobal structure with a catalytic core ribonuclear protein and a H and ACA box ribonuclear protein 8 , 9 . Here we report cryo-electron microscopy structures of human telomerase catalytic core of telomerase reverse transcriptase (TERT) and telomerase RNA (TER (also known as hTR)), and of telomerase with the shelterin protein TPP1. TPP1 forms a structured interface with the TERT-unique telomerase essential N-terminal domain (TEN) and the telomerase RAP motif (TRAP) that are unique to TERT, and conformational dynamics of TEN–TRAP are damped upon TPP1 binding, defining the requirements for recruitment and activation. The structures further reveal that the elements of TERT and TER that are involved in template and telomeric DNA handling—including the TEN domain and the TRAP–thumb helix channel—are largely structurally homologous to those in Tetrahymena telomerase 10 , and provide unique insights into the mechanism of telomerase activity. The binding site of the telomerase inhibitor BIBR1532 11 , 12 overlaps a critical interaction between the TER pseudoknot and the TERT thumb domain. Numerous mutations leading to telomeropathies 13 , 14 are located at the TERT–TER and TEN–TRAP–TPP1 interfaces, highlighting the importance of TER–TERT and TPP1 interactions for telomerase activity, recruitment and as drug targets. Cryo-electron microscopy structures of human telomerase and telomerase in complex with TPP1 provide insights into the interactions of these proteins and their activities.

Aerosol optical depth (AOD) has become a crucial metric for assessing global climate change. Although global and regional AOD trends have been studied extensively, it remains unclear what factors are driving the inter-decadal variations in regional AOD and how to quantify the relative contribution of each dominant factor. This study used a long-term (1980–2016) aerosol dataset from the Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2) reanalysis, along with two satellite-based AOD datasets (MODIS/Terra and MISR) from 2001 to 2016, to investigate the long-term trends in global and regional aerosol loading. Statistical models based on emission factors and meteorological parameters were developed to identify the main factors driving the inter-decadal changes of regional AOD and to quantify their contribution. Evaluation of the MERRA-2 AOD with the ground-based measurements of AERONET indicated significant spatial agreement on the global scale (r= 0.85, root-mean-square error = 0.12, mean fractional error = 38.7 %, fractional gross error = 9.86 % and index of agreement = 0.94). However, when AOD observations from the China Aerosol Remote Sensing Network (CARSNET) were employed for independent verification, the results showed that MERRA-2 AODs generally underestimated CARSNET AODs in China (relative mean bias = 0.72 and fractional gross error =−34.3 %). In general, MERRA-2 was able to quantitatively reproduce the annual and seasonal AOD trends on both regional and global scales, as observed by MODIS/Terra, although some differences were found when compared to MISR. Over the 37-year period in this study, significant decreasing trends were observed over Europe and the eastern United States. In contrast, eastern China and southern Asia showed AOD increases, but the increasing trend of the former reversed sharply in the most recent decade. The statistical analyses suggested that the meteorological parameters explained a larger proportion of the AOD variability (20.4 %–72.8 %) over almost all regions of interest (ROIs) during 1980–2014 when compared with emission factors (0 %–56 %). Further analysis also showed that SO2 was the dominant emission factor, explaining 12.7 %–32.6 % of the variation in AOD over anthropogenic-aerosol-dominant regions, while black carbon or organic carbon was the leading factor over the biomass-burning-dominant (BBD) regions, contributing 24.0 %–27.7 % of the variation. Additionally, wind speed was found to be the leading meteorological parameter, explaining 11.8 %–30.3 % of the variance over the mineral-dust-dominant regions, while ambient humidity (including soil moisture and relative humidity) was the top meteorological parameter over the BBD regions, accounting for 11.7 %–35.5 % of the variation. The results of this study indicate that the variation in meteorological parameters is a key factor in determining the inter-decadal change in regional AOD.

Multi-year observations of aerosol microphysical and optical properties, obtained through ground-based remote sensing at 50 China Aerosol Remote Sensing Network (CARSNET) sites, were used to characterize the aerosol climatology for representative remote, rural, and urban areas over China to assess effects on climate. The annual mean effective radii for total particles (ReffT) decreased from north to south and from rural to urban sites, and high total particle volumes were found at the urban sites. The aerosol optical depth at 440 nm (AOD440 nm) increased from remote and rural sites (0.12) to urban sites (0.79), and the extinction Ångström exponent (EAE440–870 nm) increased from 0.71 at the arid and semi-arid sites to 1.15 at the urban sites, presumably due to anthropogenic emissions. Single-scattering albedo (SSA440 nm) ranged from 0.88 to 0.92, indicating slightly to strongly absorbing aerosols. Absorption AOD440 nm values were 0.01 at the remote sites versus 0.07 at the urban sites. The average direct aerosol radiative effect (DARE) at the bottom of atmosphere increased from the sites in the remote areas (−24.40 W m−2) to the urban areas (−103.28 W m−2), indicating increased cooling at the latter. The DARE for the top of the atmosphere increased from −4.79 W m−2 at the remote sites to −30.05 W m−2 at the urban sites, indicating overall cooling effects for the Earth–atmosphere system. A classification method based on SSA440 nm, fine-mode fraction (FMF), and EAE440–870 nm showed that coarse-mode particles (mainly dust) were dominant at the rural sites near the northwestern deserts, while light-absorbing, fine-mode particles were important at most urban sites. This study will be important for understanding aerosol climate effects and regional environmental pollution, and the results will provide useful information for satellite validation and the improvement of climate modelling.

The joint configurations of prefabricated segmental cap beams exhibit considerable diversity in engineering applications. In recent years, combined shear key corbel connections have been increasingly adopted due to their advantages in prefabrication efficiency, rapid assembly, and favorable mechanical performance. Nevertheless, research on their ultimate shear capacity remains limited. To systematically assess the effects of joint configuration on shear performance, two types of cap beam models were developed reflecting engineering loading characteristics dominated by positive shear with secondary negative shear effects: a shear key model (SK1) and two keyed corbel models (SK2 and SK3), subjected to positive and negative loading, respectively. A full nonlinear static analysis with progressive loading to failure was conducted to obtain cracking load, ultimate capacity, stress distribution, deflection, and damage evolution. The results reveal that (1) all beams exhibited damage localization near adhesive joints, with shear–compression as the governing failure mode; (2) SK1 and SK2 achieved comparable shear capacities, whereas SK3 reached less than 30% of their ultimate strength; (3) SK2 attained the highest ultimate capacity, 1.07 times that of SK1; and (4) SK2 reached a maximum deflection of 3.24 mm, exceeding the other two by more than 29%. Overall, the keyed corbel configuration (SK2) demonstrated the most favorable comprehensive shear performance.

Telomerase is unique among the reverse transcriptases in containing a noncoding RNA (known as telomerase RNA (TER)) that includes a short template that is used for the processive synthesis of G-rich telomeric DNA repeats at the 3′ ends of most eukaryotic chromosomes 1 . Telomerase maintains genomic integrity, and its activity or dysregulation are critical determinants of human longevity, stem cell renewal and cancer progression 2 , 3 . Previous cryo-electron microscopy structures have established the general architecture, protein components and stoichiometries of Tetrahymena and human telomerase, but our understandings of the details of DNA–protein and RNA–protein interactions and of the mechanisms and recruitment involved remain limited 4 – 6 . Here we report cryo-electron microscopy structures of active Tetrahymena telomerase with telomeric DNA at different steps of nucleotide addition. Interactions between telomerase reverse transcriptase (TERT), TER and DNA reveal the structural basis of the determination of the 5′ and 3′ template boundaries, handling of the template–DNA duplex and separation of the product strand during nucleotide addition. The structure and binding interface between TERT and telomerase protein p50 (a homologue of human TPP1 7 , 8 ) define conserved interactions that are required for telomerase activation and recruitment to telomeres. Telomerase La-related protein p65 remodels several regions of TER, bridging the 5′ and 3′ ends and the conserved pseudoknot to facilitate assembly of the TERT–TER catalytic core. Cryo-electron microscopy structures of Tetrahymena telomerase with telomeric DNA at several steps of nucleotide addition provide insights into the structural basis of telomere repeat synthesis.