Large-scale multiplexed mosaic CRISPR perturbation in the whole organism.

Here, we report inducible mosaic animal for perturbation (iMAP), a transgenic platform enabling in situ CRISPR targeting of at least 100 genes in parallel throughout the mouse body. iMAP combines Cre-loxP and CRISPR-Cas9 technologies and utilizes a germline-transmitted transgene carrying a large array of individually floxed, tandemly linked gRNA-coding units. Cre-mediated recombination triggers expression of all the gRNAs in the array but only one of them per cell, converting the mice to mosaic organisms suitable for phenotypic characterization and also for high-throughput derivation of conventional single-gene perturbation lines via breeding. Using gRNA representation as a readout, we mapped a miniature Perturb-Atlas cataloging the perturbations of 90 genes across 39 tissues, which yields rich insights into context-dependent gene functions and provides a glimpse of the potential of iMAP in genome decoding.

Structural insights into auxin recognition and efflux by Arabidopsis PIN1.

Polar auxin transport is unique to plants and coordinates their growth and development1,2. The PIN-FORMED (PIN) auxin transporters exhibit highly asymmetrical localizations at the plasma membrane and drive polar auxin transport3,4; however, their structures and transport mechanisms remain largely unknown. Here, we report three inward-facing conformation structures of Arabidopsis thaliana PIN1: the apo state, bound to the natural auxin indole-3-acetic acid (IAA), and in complex with the polar auxin transport inhibitor N-1-naphthylphthalamic acid (NPA). The transmembrane domain of PIN1 shares a conserved NhaA fold5. In the substrate-bound structure, IAA is coordinated by both hydrophobic stacking and hydrogen bonding. NPA competes with IAA for the same site at the intracellular pocket, but with a much higher affinity. These findings inform our understanding of the substrate recognition and transport mechanisms of PINs and set up a framework for future research on directional auxin transport, one of the most crucial processes underlying plant development.

A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy.

BACKGROUND: A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL. METHODS: In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed. RESULTS: Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was -2.7±1.8, 0.2±1.7, -1.5±1.8, and -7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group. CONCLUSIONS: In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo. (Funded by Visterra; ENVISION ClinicalTrials.gov number, NCT04287985; EudraCT number, 2019-002531-29.).

Longitudinal mapping of the development of cortical thickness and surface area in rhesus macaques during the first three years.

Studying dynamic spatiotemporal patterns of early brain development in macaque monkeys is critical for understanding the cortical organization and evolution in humans, given the phylogenetic closeness between humans and macaques. However, due to huge challenges in the analysis of early brain Magnetic Resonance Imaging (MRI) data typically with extremely low contrast and dynamic imaging appearances, our knowledge of the early macaque cortical development remains scarce. To fill this critical gap, this paper characterizes the early developmental patterns of cortical thickness and surface area in rhesus macaques by leveraging advanced computing tools tailored for early developing brains based on a densely sampled longitudinal dataset with 140 rhesus macaque MRI scans seamlessly covering from birth to 36 mo of age. The average cortical thickness exhibits an inverted U-shaped trajectory with peak thickness at around 4.3 mo of age, which is remarkably in line with the age of peak thickness at 14 mo in humans, considering the around 3:1 age ratio of human to macaque. The total cortical surface area in macaques increases monotonically but with relatively lower expansions than in humans. The spatial distributions of thicker and thinner regions are quite consistent during development, with gyri having a thicker cortex than sulci. By 4 mo of age, over 81% of cortical vertices have reached their peaks in thickness, except for the insula and medial temporal cortices, while most cortical vertices keep expanding in surface area, except for the occipital cortex. These findings provide important insights into early brain development and evolution in primates.

TRAF2 decrease promotes the TGF-ß-mTORC1 signal in MAFLD-HCC through enhancing AXIN1-mediated Smad7 degradation.

According to recent research, metabolic-associated fatty liver disease (MAFLD) has emerged as an important underlying etiology of hepatocellular carcinoma (HCC). However, the molecular mechanism of MAFLD-HCC is still unclear. Tumor necrosis factor receptor-associated factor 2 (TRAF2) is the key molecule to mediate the signal of inflammatory NF-κB pathway. This study aims to investigate the potential dysregulation of TRAF2 and its biological function in MAFLD-HCC. Huh7 TRAF2-/- demonstrated increased tumor formation ability compared to huh7 TRAF2+/+ when stimulated with transforming growth factor-ß (TGF-ß). The decisive role of TGF-ß in the development of MAFLD-HCC was confirmed through the specific depletion of TGF-ß receptor II gene in the hepatocytes (Tgfbr2ΔHep) of mice. In TRAF2-/- cells treated with TGF-ß, both the glycolysis rate and lipid synthesis were enhanced. We proved the signal of the mechanistic target of rapamycin complex 1 (mTORC1) could be activated in the presence of TGF-ß, and was enhanced in TRAF2-/- cells. The coimmunoprecipitation (co-IP) experiments revealed that TRAF2 fortified the Smurf2-mediated ubiquitination degradation of AXIN1. Hence, TRAF2 depletion resulted in increased Smad7 degradation induced by AXIN1, thus promoting the TGF-ß signal. We also discovered that PLX-4720 could bind with AXIN1 and restrained the tumor proliferation of TRAF2-/- in mice fed with high-fat diet (HFD). Our findings indicate that TRAF2 plays a significant role in the pathogenesis of MAFLD-HCC. The reduction of TRAF2 expression leads to the enhancement of the TGF-ß-mTORC1 pathway by facilitating AXIN1-mediated Smad7 degradation.

Suppression of neuronal CDK9/p53/VDAC signaling provides bioenergetic support and improves post-stroke neuropsychiatric outcomes.

Bioenergy decline occurs with reperfusion following acute ischemic stroke. However, the molecular mechanisms that limit energy metabolism and their impact on post-stroke cognitive and emotional complications are still unclear. In the present study, we demonstrate that the p53 transcriptional response is responsible for neuronal adenosine triphosphate (ATP) deficiency and progressively neuropsychiatric disturbances, involving the downregulation of mitochondrial voltage-dependent anion channels (VDACs). Neuronal p53 transactivated the promoter of microRNA-183 (miR-183) cluster, thereby upregulating biogenesis of miR-183-5p (miR-183), miR-96-5p (miR-96), and miR-182-5p. Both miR-183 and miR-96 directly targeted and post-transcriptionally suppressed VDACs. Neuronal ablation of p53 protected against ATP deficiency and neurological deficits, whereas post-stroke rescue of miR-183/VDAC signaling reversed these benefits. Interestingly, cyclin-dependent kinase 9 (CDK9) was found to be enriched in cortical neurons and upregulated the p53-induced transcription of the miR-183 cluster in neurons after ischemia. Post-treatment with the CDK9 inhibitor oroxylin A promoted neuronal ATP production mainly through suppressing the miR-183 cluster/VDAC axis, further improved long-term sensorimotor abilities and spatial memory, and alleviated depressive-like behaviors in mice following stroke. Our findings reveal an intrinsic CDK9/p53/VDAC pathway that drives neuronal bioenergy decline and underlies post-stroke cognitive impairment and depression, thus highlighting the therapeutic potential of oroxylin A for better outcomes.

CASK and FARP localize two classes of post-synaptic ACh receptors thereby promoting cholinergic transmission.

Changes in neurotransmitter receptor abundance at post-synaptic elements play a pivotal role in regulating synaptic strength. For this reason, there is significant interest in identifying and characterizing the scaffolds required for receptor localization at different synapses. Here we analyze the role of two C. elegans post-synaptic scaffolding proteins (LIN-2/CASK and FRM-3/FARP) at cholinergic neuromuscular junctions. Constitutive knockouts or muscle specific inactivation of lin-2 and frm-3 dramatically reduced spontaneous and evoked post-synaptic currents. These synaptic defects resulted from the decreased abundance of two classes of post-synaptic ionotropic acetylcholine receptors (ACR-16/CHRNA7 and levamisole-activated AChRs). LIN-2's AChR scaffolding function is mediated by its SH3 and PDZ domains, which interact with AChRs and FRM-3/FARP, respectively. Thus, our findings show that post-synaptic LIN-2/FRM-3 complexes promote cholinergic synaptic transmission by recruiting AChRs to post-synaptic elements.

A Biphasic Strategy to Synergistically Accelerate Activation and CO Spillover in Formic Acid Oxidation Catalysis.

Developing highly efficient and carbon monoxide (CO)-tolerant platinum (Pt) catalysts for the formic acid oxidation reaction (FAOR) is vital for direct formic acid fuel cells (DFAFCs), yet it is challenging due to the high energy barrier of direct intermediates (HCOO* and COOH*) as well as the CO poisoning issues associated with Pt alloy catalysts. Here we present a versatile biphasic strategy by creating a hexagonal/cubic crystalline-phase-synergistic PtPb/C (h/c-PtPb/C) catalyst to tackle the aforementioned issues. Detailed investigations reveal that h/c-PtPb/C can simultaneously facilitate the adsorption of direct intermediates while inhibiting CO adsorption, thereby significantly improving the activation and CO spillover. As a result, h/c-PtPb/C showcases an outstanding FAOR activity of 8.1 A mgPt-1, which is 64.5 times higher than that of commercial Pt/C and significantly surpasses monophasic PtPb. Moreover, the h/c-PtPb/C-based membrane electrode assembly exhibits an exceptional peak power density of 258.7 mW cm-2 for practical DFAFC applications.

Amorphization Activated Multimetallic Pd Alloys for Boosting Oxygen Reduction Catalysis.

Amorphous nanomaterials have drawn extensive attention owing to their unique features, while amorphization on noble metal nanomaterials still remains formidably challenging. Herein, we demonstrate a universal strategy to synthesize amorphous Pd-based nanomaterials from unary to quinary metals through the introduction of phosphorus (P). The amorphous Pd-based nanoparticles (NPs) exhibit generally promoted oxygen reduction reaction (ORR) activity and durability compared with their crystalline counterparts. Significantly, the quinary P-PdCuNiInSn NPs, benefiting from the amorphous structure and multimetallic component effect, exhibit mass activities as high as 1.04 A mgPd-1 and negligible activity decays of 1.8% among the stability tests, which are much better than values for original Pd NPs (0.134 A mgPd-1 and 28.4%). Experimental and theoretical analyses collectively reveal that the synergy of P-induced amorphization and the expansion of metallic components can considerably lower the free energy changes in the rate-determined step, thereby explaining the positive correlation with the catalytic activity.

Post-transcriptional regulation of mouse neurogenesis by Pumilio proteins.

Despite extensive studies on mammalian neurogenesis, its post-transcriptional regulation remains under-explored. Here we report that neural-specific inactivation of two murine post-transcriptional regulators, Pumilio 1 (Pum1) and Pum2, severely reduced the number of neural stem cells (NSCs) in the postnatal dentate gyrus (DG), drastically increased perinatal apoptosis, altered DG cell composition, and impaired learning and memory. Consistently, the mutant DG neurospheres generated fewer NSCs with defects in proliferation, survival, and differentiation, supporting a major role of Pum1 and Pum2 in hippocampal neurogenesis and function. Cross-linking immunoprecipitation revealed that Pum1 and Pum2 bind to thousands of mRNAs, with at least 694 common targets in multiple neurogenic pathways. Depleting Pum1 and/or Pum2 did not change the abundance of most target mRNAs but up-regulated their proteins, indicating that Pum1 and Pum2 regulate the translation of their target mRNAs. Moreover, Pum1 and Pum2 display RNA-dependent interaction with fragile X mental retardation protein (FMRP) and bind to one another's mRNA. This indicates that Pum proteins might form collaborative networks with FMRP and possibly other post-transcriptional regulators to regulate neurogenesis.

Cell-permeable JNK-inhibitory peptide regulates intestinal barrier function and inflammation to ameliorate necrotizing enterocolitis.

Intestinal dysbiosis is believed to play a role in the development of necrotizing enterocolitis (NEC). The efficacy of JNK-inhibitory peptide (CPJIP) in treating NEC was assessed. Treatment with CPJIP led to a notable reduction in p-JNK expression in IEC-6 cells and NEC mice. Following LPS stimulation, the expression of RNA and protein of claudin-1, claudin-3, claudin-4 and occludin was significantly decreased, with this decrease being reversed by CPJIP administration, except for claudin-3, which remained consistent in NEC mice. Moreover, the expression levels of the inflammatory factors TNF-α, IL-1ß and IL-6 were markedly elevated, a phenomenon that was effectively mitigated by the addition of CPJIP in both IEC-6 cells and NEC mice. CPJIP administration resulted in improved survival rates, ameliorated microscopic intestinal mucosal injury, and increased the total length of the intestines and colon in NEC mice. Additionally, CPJIP treatment led to a reduction in serum concentrations of FD-4, D-lactate and DAO. Furthermore, our results revealed that CPJIP effectively inhibited intestinal cell apoptosis and promoted cell proliferation in the intestine. This study represents the first documentation of CPJIP's ability to enhance the expression of tight junction components, suppress inflammatory responses, and rescue intestinal cell fate by inhibiting JNK activation, ultimately mitigating intestinal severity. These findings suggest that CPJIP has the potential to serve as a promising candidate for the treatment of NEC.

Enhanced Superconductivity and Critical Current Density Due to the Interaction of InSe2 Bonded Layer in (InSe2)0.12NbSe2.

Superconductivity was discovered in (InSe2)xNbSe2. The materials are crystallized in a unique layered structure where bonded InSe2 layers are intercalated into the van der Waals gaps of 2H-phase NbSe2. The (InSe2)0.12NbSe2 superconductor exhibits a superconducting transition at 11.6 K and critical current density of 8.2 × 105 A/cm2. Both values are the highest among all transition metal dichalcogenide superconductors at ambient pressure. The present finding provides an ideal material platform for further investigation of superconducting-related phenomena in transition metal dichalcogenides.

Metal-Sulfur Interfaces as the Primary Active Sites for Catalytic Hydrogenations.

The determination of catalytically active sites is crucial for understanding the catalytic mechanism and providing guidelines for the design of more efficient catalysts. However, the complex structure of supported metal nanocatalysts (e.g., support, metal surface, and metal-support interface) still presents a big challenge. In particular, many studies have demonstrated that metal-support interfaces could also act as the primary active sites in catalytic reactions, which is well elucidated in oxide-supported metal nanocatalysts but is rarely reported in carbon-supported metal nanocatalysts. Here, we fill the above gap and demonstrate that metal-sulfur interfaces in sulfur-doped carbon-supported metal nanocatalysts are the primary active sites for several catalytic hydrogenation reactions. A series of metal nanocatalysts with similar sizes but different amounts of metal-sulfur interfaces were first constructed and characterized. Taking Ir for quinoline hydrogenation as an example, it was found that their catalytic activities were proportional to the amount of the Ir-S interface. Further experiments and density functional theory (DFT) calculations suggested that the adsorption and activation of quinoline occurred on the Ir atoms at the Ir-S interface. Similar phenomena were found in p-chloronitrobenzene hydrogenation over the Pt-S interface and benzoic acid hydrogenation over the Ru-S interface. All of these findings verify the predominant activity of metal-sulfur interfaces for catalytic hydrogenation reactions and contribute to the comprehensive understanding of metal-support interfaces in supported nanocatalysts.

Screening of Intermetallic Compounds Based on Intermediate Adsorption Equilibrium for Electrocatalytic Nitrate Reduction to Ammonia.

Electrocatalytic nitrate (NO3-) reduction reaction (NO3RR) holds great potential for the conversion of NO3- contaminants into valuable NH3 in a sustainable method. Unfortunately, the nonequilibrium adsorption of intermediates and sluggish multielectron transfer have detrimental impacts on the electrocatalytic performance of the NO3RR, posing obstacles to its practical application. Herein, we initially screen the adsorption energies of three key intermediates, i.e., *NO3, *NO, and *H2O, along with the d-band centers on 21 types of transition metal (IIIV and IB)-Sb/Bi-based intermetallic compounds (IMCs) as electrocatalysts. The results reveal that hexagonal CoSb IMCs possess the optimal adsorption equilibrium for key intermediates and exhibit outstanding electrocatalytic NO3RR performance with a Faradaic efficiency of 96.3%, a NH3 selectivity of 89.1%, and excellent stability, surpassing the majority of recently reported NO3RR electrocatalysts. Moreover, the integration of CoSb IMCs/C into a novel Zn-NO3- battery results in a high power density of 11.88 mW cm-2.

Heterophase Intermetallic Compounds for Electrocatalytic Hydrogen Production at Industrial-Scale Current Densities.

Heterophase nanomaterials have sparked significant research interest in catalysis due to their distinctive properties arising from synergistic effects of different components and the formed phase boundary. However, challenges persist in the controlled synthesis of heterophase intermetallic compounds (IMCs), primarily due to the lattice mismatch of distinct crystal phases and the difficulty in achieving precise control of the phase transitions. Herein, orthorhombic/cubic Ru2Ge3/RuGe IMCs with engineered boundary architecture are synthesized and anchored on the reduced graphene oxide. The Ru2Ge3/RuGe IMCs exhibit excellent hydrogen evolution reaction (HER) performance with a high current density of 1000 mA cm-2 at a low overpotential of 135 mV. The presence of phase boundaries enhances charge transfer and improves the kinetics of water dissociation while optimizing the processes of hydrogen adsorption/desorption, thus boosting the HER performance. Moreover, an anion exchange membrane electrolyzer is constructed using Ru2Ge3/RuGe as the cathode electrocatalyst, which achieves a current density of 1000 mA cm-2 at a low voltage of 1.73 V, and the activity remains virtually undiminished over 500 h.

MIWI prevents aneuploidy during meiosis by cleaving excess satellite RNA.

MIWI, a murine member of PIWI proteins mostly expressed during male meiosis, is crucial for piRNA biogenesis, post-transcriptional regulation, and spermiogenesis. However, its meiotic function remains unknown. Here, we report that MIWI deficiency alters meiotic kinetochore assembly, significantly increases chromosome misalignment at the meiosis metaphase I plate, and causes chromosome mis-segregation. Consequently, Miwi-deficient mice show elevated aneuploidy in metaphase II and spermatid death. Furthermore, in Miwi-null and Miwi slicer-deficient mutants, major and minor satellite RNAs from centromeric and pericentromeric satellite repeats accumulate in excess. Over-expression of satellite repeats in wild-type spermatocytes also causes elevated chromosome misalignment, whereas reduction of both strands of major or minor satellite RNAs results in lower frequencies of chromosome misalignment. We show that MIWI, guided by piRNA, cleaves major satellite RNAs, generating RNA fragments that may form substrates for subsequent Dicer cleavage. Furthermore, Dicer cleaves all satellite RNAs in conjunction with MIWI. These findings reveal a novel mechanism in which MIWI- and Dicer-mediated cleavage of the satellite RNAs prevents the over-expression of satellite RNAs, thus ensuring proper kinetochore assembly and faithful chromosome segregation during meiosis.

A WDR47 homolog facilitates ciliogenesis by modulating intraflagellar transport.

Cilia are conserved organelles found in many cell types in eukaryotes, and their dysfunction causes defects in environmental sensing and signaling transduction; such defects are termed ciliopathies. Distinct cilia have cell-specific morphologies and exert distinct functions. However, the underlying mechanisms of cell-specific ciliogenesis and regulation are unclear. Here, we identified a WD40-repeat (WDR) protein, NMTN-1 (the homolog of mammalian WDR47), and show that it is specifically required for ciliogenesis of AWB chemosensory neurons in C. elegans. NMTN-1 is expressed in the AWB chemosensory neuron pair, and is enriched at the basal body (BB) of the AWB cilia. Knockout of nmtn-1 causes abnormal AWB neuron cilia morphology, structural integrity, and induces aberrant AWB-mediated aversive behaviors. We further demonstrate that nmtn-1 deletion affects movement of intraflagellar transport (IFT) particles and their cargo delivery in AWB neurons. Our results indicate that NMTN-1 is essential for AWB neuron ciliary morphology and function, which reveal a novel mechanism for cell-specific ciliogenesis. Given that WDR47/NMTN-1 is conserved in mammals, our findings may help understanding of the process of cell-specific ciliogenesis and provide insights for treating ciliopathies.

Third-generation sequencing revises the molecular karyotype for Toxoplasma gondii and identifies emerging copy number variants in sexual recombinants.

Toxoplasma gondii is a useful model for intracellular parasitism given its ease of culture in the laboratory and genomic resources. However, as for many other eukaryotes, the T. gondii genome contains hundreds of sequence gaps owing to repetitive and/or unclonable sequences that disrupt the assembly process. Here, we use the Oxford Nanopore Minion platform to generate near-complete de novo genome assemblies for multiple strains of T. gondii and its near relative, N. caninum We significantly improved T. gondii genome contiguity (average N50 of ∼6.6 Mb) and added ∼2 Mb of newly assembled sequence. For all of the T. gondii strains that we sequenced (RH, ME49, CTG, II×III progeny clones CL13, S27, S21, S26, and D3X1), the largest contig ranged in size between 11.9 and 12.1 Mb in size, which is larger than any previously reported T. gondii chromosome, and found to be due to a consistent fusion of Chromosomes VIIb and VIII. These data were validated by mapping existing T. gondii ME49 Hi-C data to our assembly, providing parallel lines of evidence that the T. gondii karyotype consists of 13, rather than 14, chromosomes. By using this technology, we also resolved hundreds of tandem repeats of varying lengths, including in well-known host-targeting effector loci like rhoptry protein 5 (ROP5) and ROP38 Finally, when we compared T. gondii with N. caninum, we found that although the 13-chromosome karyotype was conserved, extensive, previously unappreciated chromosome-scale rearrangements had occurred in T. gondii and N. caninum since their most recent common ancestry.

Integrative analysis of the transcriptome and proteome reveals the molecular responses of tobacco to boron deficiency.

BACKGROUND: Boron (B) is an essential micronutrient for plants. Inappropriate B supply detrimentally affects the productivity of numerous crops. Understanding of the molecular responses of plants to different B supply levels would be of significance in crop improvement and cultivation practices to deal with the problem. RESULTS: We conducted a comprehensive analysis of the transcriptome and proteome of tobacco seedlings to investigate the expression changes of genes/proteins in response to different B supply levels, with a particular focus on B deficiency. The global gene and protein expression profiles revealed the potential mechanisms involved in the responses of tobacco to B deficiency, including up-regulation of the NIP5;1-BORs module, complex regulation of genes/proteins related to cell wall metabolism, and up-regulation of the antioxidant machinery. CONCLUSION: Our results demonstrated that B deficiency caused severe morphological and physiological disorders in tobacco seedlings, and revealed dynamic expression changes of tobacco genes/proteins in response to different B supply levels, especially to B deficiency, thus offering valuable insights into the molecular responses of tobacco to B deficiency.

Stabilizing 4.6 V LiCoO2 via Er and Mg Trace Doping at Li-Site and Co-Site Respectively.

Charging LiCoO2 to high voltages yields alluring specific capacities, yet the deleterious phase-transitions lead to significant capacity degradation. Herein, this study demonstrates a novel strategy to stabilize LiCoO2 at 4.6 V by doping with Er and Mg at the Li-site and Co-site, respectively, which is different from the traditional method of doping foreign elements solely at the Co-site. Theoretical calculations and experiments jointly reveal that the inclusion of Mg2+-dopants at the Co-site curbs the hexagonal-monoclinic phase transitions ≈4.2 V. However, this unintentionally compromises the stability of lattice oxygen in LiCoO2, exacerbating the undesired phase transition (O3 to H1-3) above 4.45 V. Fascinatingly, the introduction of Er3+-dopants into Li-sites enhances the stability of lattice oxygen in LiCoO2, effectively mitigating phase transitions above 4.45 V. Therefore, the Er, Mg co-doped LiCoO2 exhibits high stability over 500 cycles when tested in a half-cell with a cut-off voltage of 4.6 V. Furthermore, the Er, Mg-doped LiCoO2//graphite pouch-type full cell demonstrates a high energy density of 310.8 Wh kg-1, preserving 91.3% of its energy over 100 cycles.