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N 6 -methyladenosine (m 6 A), the most prevalent internal RNA modification on mammalian messenger RNAs, regulates the fates and functions of modified transcripts through m 6 A-specific binding proteins 1 – 5 . In the nervous system, m 6 A is abundant and modulates various neural functions 6 – 11 . Whereas m 6 A marks groups of mRNAs for coordinated degradation in various physiological processes 12 – 15 , the relevance of m 6 A for mRNA translation in vivo remains largely unknown. Here we show that, through its binding protein YTHDF1, m 6 A promotes protein translation of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory. Mice with genetic deletion of Ythdf1 show learning and memory defects as well as impaired hippocampal synaptic transmission and long-term potentiation. Re-expression of YTHDF1 in the hippocampus of adult Ythdf1 -knockout mice rescues the behavioural and synaptic defects, whereas hippocampus-specific acute knockdown of Ythdf1 or Mettl3 , which encodes the catalytic component of the m 6 A methyltransferase complex, recapitulates the hippocampal deficiency. Transcriptome-wide mapping of YTHDF1-binding sites and m 6 A sites on hippocampal mRNAs identified key neuronal genes. Nascent protein labelling and tether reporter assays in hippocampal neurons showed that YTHDF1 enhances protein synthesis in a neuronal-stimulus-dependent manner. In summary, YTHDF1 facilitates translation of m 6 A-methylated neuronal mRNAs in response to neuronal stimulation, and this process contributes to learning and memory. Neuronal stimulation induces protein translation of m 6 A-methylated neuronal mRNAs facilitated by YTHDF1, and this process contributes to learning and memory.

A recently developed adenine base editor (ABE) efficiently converts A to G and is potentially useful for clinical applications. However, its precision and efficiency in vivo remains to be addressed. Here we achieve A-to-G conversion in vivo at frequencies up to 100% by microinjection of ABE mRNA together with sgRNAs. We then generate mouse models harboring clinically relevant mutations at Ar and Hoxd13 , which recapitulates respective clinical defects. Furthermore, we achieve both C-to-T and A-to-G base editing by using a combination of ABE and SaBE3, thus creating mouse model harboring multiple mutations. We also demonstrate the specificity of ABE by deep sequencing and whole-genome sequencing (WGS). Taken together, ABE is highly efficient and precise in vivo, making it feasible to model and potentially cure relevant genetic diseases. CRISPR-based base editors allow for single nucleotide genome editing in a range of organisms. Here the authors demonstrate the in vivo generation of mouse models carrying clinically relevant mutations using C→T and A→G editors.

Autism spectrum disorder (ASD) is a neurodevelopmental disease with a strong heritability, but recent evidence suggests that epigenetic dysregulation may also contribute to the pathogenesis of ASD. Especially, increased methylation at the MECP2 promoter and decreased MECP2 expression were observed in the brains of ASD patients. However, the causative relationship of MECP2 promoter methylation and ASD has not been established. In this study, we achieved locus-specific methylation at the transcription start site (TSS) of Mecp2 in Neuro-2a cells and in mice, using nuclease-deactivated Cas9 (dCas9) fused with DNA methyltransferase catalytic domains, together with five locus-targeting sgRNAs. This locus-specific epigenetic modification led to a reduced Mecp2 expression and a series of behavioral alterations in mice, including reduced social interaction, increased grooming, enhanced anxiety/depression, and poor performance in memory tasks. We further found that specifically increasing the Mecp2 promoter methylation in the hippocampus was sufficient to induce most of the behavioral changes. Our finding therefore demonstrated for the first time the casual relationship between locus-specific DNA methylation and diseases symptoms in vivo, warranting potential therapeutic application of epigenetic editing.

A bstract Exotic neutral gauge bosons are powerful candidates for new physics beyond the Standard Model. The Left-Right Symmetric Model is a well-motivated framework that addresses several open questions in particle physics, including neutrino masses, dark matter, and the matter-antimatter asymmetry. It predicts new gauge bosons, such as Z ′ and W ′± , along with additional right-handed particles. We investigate the processes μ + μ − → q q ¯ and μ + μ − → l + l − with the Z ′ boson appearing as an intermediate state. The coupling strength, decay width and mass are the key parameters that govern the production and decay of the Z ′ boson. The results indicate that the angular distributions of final-state particles are sensitive to the couplings of Z ′ to the other fermions. The forward-backward asymmetry, derived from angular distributions, serves as a sensitive observable for distinguishing Standard Model predictions from those involving Z ′ exchange. It also provides a powerful probe of the Z ′ couplings to fermions. Compared with the current results at the Large Hadron Collider (LHC), the future muon collider has great potential to explore new parameter space with the Z ′ boson.

The design and screening of sgRNA in CRISPR-dependent gene knock-in is always laborious. Therefore, a universal and highly efficient knock-in strategy suitable for different sgRNA target sites is necessary. In our mouse embryo study, we find that the knock-in efficiency guided by adjacent sgRNAs varies greatly, although similar indel frequency. MMEJ-biased sgRNAs usually lead to high knock-in efficiency, whereas NHEJ-biased sgRNAs result in low knock-in efficiency. Blocking MMEJ repair by knocking down Polq can enhance knock-in efficiency, but inhibiting NHEJ repair shows variable effects. We identify a compound, AZD7648, that can shift DSBs repair towards MMEJ. Finally, by combining AZD7648 treatment with Polq knockdown, we develop a universal and highly efficient knock-in strategy in mouse embryos. This approach is validated at more than ten genomic loci, achieving up to 90% knock-in efficiency, marking a significant advancement toward predictable and highly efficient CRISPR-mediated gene integration. Precise CRISPR-based gene knock-in is often limited by variable efficiency across sgRNAs. Here, the authors develop ChemiCATI, a universal strategy combining Polq knockdown and AZD7648 treatment, enabling efficient and predictable integration across multiple loci in mouse embryos.

The neutrinophilic two Higgs doublet model is one of the simplest models to explain the origin of tiny Dirac neutrino masses. This model introduces a new Higgs doublet with eV scale VEV to naturally generate the tiny neutrino masses. Depending on the same Yukawa coupling, the neutrino oscillation patterns can be probed with the dilepton signature from the decay of charged scalar H ± . For example, the normal hierarchy predicts BR ( H + → e + ν ) ≪ BR ( H + → μ + ν ) ≈ BR ( H + → τ + ν ) ≃ 0.5 when the lightest neutrino mass is below 0.01 eV, while the inverted hierarchy predicts BR ( H + → e + ν ) / 2 ≃ BR ( H + → μ + ν ) ≃ BR ( H + → τ + ν ) ≃ 0.25 . By precise measurement of BR ( H + → ℓ + ν ) , we are hopefully to probe the lightest neutrino mass and the atmospheric mixing angle θ 23 . Through the detailed simulation of the dilepton signature and corresponding backgrounds, we find that the 3 TeV CLIC could discover M H + ≲ 1220  GeV for NH and M H + ≲ 1280  GeV for IH. Meanwhile, the future 100 TeV FCC-hh collider could probe M H + ≲ 1810  GeV for NH and M H + ≲ 2060  GeV for IH.

The efficiency of homology-directed repair (HDR) plays a crucial role in the development of animal models and gene therapy. We demonstrate that microhomology-mediated end-joining (MMEJ) constitutes a substantial proportion of DNA repair during CRISPR-mediated gene editing. Using CasRx to downregulate a key MMEJ factor, Polymerase Q ( Polq ), we improve the targeted integration efficiency of linearized DNA fragments and single-strand oligonucleotides (ssODN) in mouse embryos and offspring. CasRX-assisted targeted integration (CATI) also leads to substantial improvements in HDR efficiency during the CRISPR/Cas9 editing of monkey embryos. We present a promising tool for generating monkey models and developing gene therapies for clinical trials.

Heavy neutral gauge boson Z ′ is proposed in many new physics models. It has rich phenomena at the future muon collider. We study the properties of Z ′ boson with the process of and μ + μ − → W + W − . The discrepancy of Z ′ coupling to different types of particles can be shown in the cross section distributions around the resonance peak of various decay modes. Angular distributions of the final quark or lepton in process are sensitive to the parameters such as mass of Z ′ and the Z − Z ′ mixing angle. The interaction of new gauge boson coupling to the standard model gauge particles and Higgs boson are also studied through and . The cross section and the final particles’ angular distributions with the contribution of Z ′ boson differ from those processes with only standard model particles. A forward-backward asymmetry defined by the angular distribution is provided to show the potential of searching for new physics at the muon collider. Especially, the beam polarization with certain value can effectively enlarge the forward-backward asymmetry.

Epigenetic information regulates gene expression and development. However, our understanding of the evolution of epigenetic regulation on brain development in primates is limited. Here, we compared chromatin accessibility landscapes and transcriptomes during fetal prefrontal cortex (PFC) development between rhesus macaques and humans. A total of 304,761 divergent DNase I-hypersensitive sites (DHSs) are identified between rhesus macaques and humans, although many of these sites share conserved DNA sequences. Interestingly, most of the cis -elements linked to orthologous genes with dynamic expression are divergent DHSs. Orthologous genes expressed at earlier stages tend to have conserved cis -elements, whereas orthologous genes specifically expressed at later stages seldom have conserved cis -elements. These genes are enriched in synapse organization, learning and memory. Notably, DHSs in the PFC at early stages are linked to human educational attainment and cognitive performance. Collectively, the comparison of the chromatin epigenetic landscape between rhesus macaques and humans suggests a potential role for regulatory elements in the evolution of differences in cognitive ability between non-human primates and humans. The evolution of epigenetic regulation of brain development in primates is not well understood. Here, the authors perform a comparative study of epigenetic dynamics of early prefrontal cortex development between human and rhesus macaque, finding divergent regulatory elements that may be related to cognitive capacity.

Base editing systems show their power in modeling and correcting the pathogenic mutations of genetic diseases. Previous studies have already demonstrated the editing efficiency of BE3-mediated C-to-T conversion in human embryos. However, the precision and efficiency of a recently developed adenine base editor (ABE), which converts A-to-G editing in human embryos, remain to be addressed. Here we selected reported pathogenic mutations to characterize the ABE in human tripronuclear embryos. We found effective A-to-G editing occurred at the desirable sites using the ABE system. Furthermore, ABE-mediated A-to-G editing in the single blastomere of the edited embryos exhibited high product purity. By deep sequencing and whole-genome sequencing, A or T mutations didn’t increase significantly, and no off-target or insertion or deletion (indel) mutations were detected in these edited embryos, indicating the ABE-mediated base editing in human embryos is precise and controllable. For some sites, since a different editing pattern was obtained from the cells and the embryos targeted with the same single guide RNA (sgRNA), it suggests that ABE-mediated editing might have different specificity in vivo. Taken together, we efficiently generated pathogenic A-to-G mutations in human tripronuclear embryos via ABE-mediated base editing.