Bioisosteric replacement strategy leads to novel DNA gyrase B inhibitors with improved potencies and properties.

The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC50 values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.

Do domestic budgerigars perceive predation risk?

Predation risk may affect the foraging behavior of birds. However, there has been little research on the ability of domestic birds to perceive predation risk and thus adjust their feeding behavior. In this study, we tested whether domestic budgerigars (Melopsittacus undulatus) perceived predation risk after the presentation of specimens and sounds of sparrowhawks (Accipiter nisus), domestic cats (Felis catus), and humans, and whether this in turn influenced their feeding behavior. When exposed to visual or acoustic stimuli, budgerigars showed significantly longer latency to feed under sparrowhawk, domestic cat, and human treatments than with controls. Budgerigars responded more strongly to acoustic stimuli than visual stimuli, and they showed the longest latency to feed and the least number of feeding times in response to sparrowhawk calls. Moreover, budgerigars showed shorter latency to feed and greater numbers of feeding times in response to human voices than to sparrowhawk or domestic cat calls. Our results suggest that domestic budgerigars may identify predation risk through visual or acoustic signals and adjust their feeding behavior accordingly.

Potential oral VEGFR2 inhibitors: Treatment of wet age-related macular degeneration.

Wet age-related macular degeneration (w-AMD) is one of the leading causes of vision loss in industrialized countries. A large body of evidence suggests that inhibitors targeting VEGFR2 may be effective in the treatment of w-AMD. The identification of an oral VEGFR2 inhibitor for the treatment of w-AMD provides an opportunity for a route of administration other than intravitreal injection. While screening potent VEGFR2 inhibitors at the enzyme and cellular levels, ensuring the safety of the compounds was our primary strategy for screening optimal compounds. Finally, compound 16 was identified, exhibiting enhanced inhibition of VEGFR2 enzyme and proliferation of BaF3-TEL-VEGFR2 cells compared to Vorolanib. Compound 16 had a weak inhibitory effect on human Ether-a-go-go-related gene (hERG) channel currents, showing a cardiac safety profile similar to Vorolanib. Compound 16 showed no significant toxicity to human liver cell LX-2, indicating a liver safety profile similar to Vorolanib. The water solubility of compound 16 was found to be higher than that of Vorolanib when tested at pH = 7.4. In addition, compound 16 was found to inhibit VEGFR2 phosphorylation in human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner by WB assay. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound 16 showed remarkable plasma stability and moderate liver microsomal stability. Based on in vivo pharmacokinetic studies in ICR mice, compound 16 exhibited acceptable oral bioavailability (F = 20.2 %). Overall, these findings provide evidence that compound 16 is a leading potential oral drug candidate for w-AMD.

Crop DNA extraction with lab-made magnetic nanoparticles.

Molecular breeding methods, such as marker-assisted selection and genomic selection, require high-throughput and cost-effective methods for isolating genomic DNA from plants, specifically from crop tissue or seed with high polysaccharides, lipids, and proteins. A quick and inexpensive high-throughput method for isolating genomic DNA from seed and leaf tissue from multiple crops was tested with a DNA isolation method that combines CTAB extraction buffer and lab-made SA-coated magnetic nanoparticles. This method is capable of isolating quality genomic DNA from leaf tissue and seeds in less than 2 hours with fewer steps than a standard CTAB extraction method. The yield of the genomic DNA was 582-729 ng per 5 leaf discs or 216-1869 ng per seed in soybean, 2.92-62.6 ng per 5 leaf discs or 78.9-219 ng per seed in wheat, and 30.9-35.4 ng per 5 leaf discs in maize. The isolated DNA was tested with multiple molecular breeding methods and was found to be of sufficient quality and quantity for PCR and targeted genotyping by sequencing methods such as molecular inversion probes (MIPs). The combination of SA-coated magnetic nanoparticles and CTAB extraction buffer is a fast, simple, and environmentally friendly, high-throughput method for both leaf tissues and seed(s) DNA preparation at low cost per sample. The DNA obtained from this method can be deployed in applied breeding programs for marker-assisted selection or genomic selection.

Design, synthesis and biological evaluation of carbamate derivatives incorporating multifunctional carrier scaffolds as pseudo-irreversible cholinesterase inhibitors for the treatment of Alzheimer's disease.

In this study, a series of carbamate derivatives incorporating multifunctional carrier scaffolds were designed, synthesized, and evaluated as potential therapeutic agents for Alzheimer's disease (AD). We used tacrine to modify the aliphatic substituent, and employed rivastigmine, indole and sibiriline fragments as carrier scaffolds. The majority of compounds exhibited good inhibitory activity for cholinesterase. Notably, compound C7 with sibiriline fragment exhibited potent inhibitory activities against human acetylcholinesterase (hAChE, IC50 = 30.35 ± 2.07 nM) and human butyrylcholinesterase (hBuChE, IC50 = 48.03 ± 6.41 nM) with minimal neurotoxicity. Further investigations have demonstrated that C7 exhibited a remarkable capacity to safeguard PC12 cells against H2O2-induced apoptosis and effectively suppressed the production of reactive oxygen species (ROS). Moreover, in an inflammation model of BV2 cells induced by lipopolysaccharide (LPS), C7 effectively attenuated the levels of pro-inflammatory cytokines. After 12 h of dialysis, C7 continued to exhibit an inhibitory effect on cholinesterase activity. An acute toxicity test in vivo demonstrated that C7 exhibited a superior safety profile and no hepatotoxicity compared to the parent nucleus tacrine. In the scopolamine-induced AD mouse model, C7 (20 mg/kg) significantly reduced cholinesterase activity in the brain of the mice. C7 was tested in a pharmacological AD mouse model induced by Aß1-42 and attenuated memory deficits at doses as low as 5 mg/kg. The pseudo-irreversible cholinesterase inhibitory properties and multifunctional therapeutic attributes of C7 render it a promising candidate for further investigation in the treatment of AD.

An α-hemoglobin-derived peptide (m)VD-hemopressin (α) promotes NREM sleep via the CB1 cannabinoid receptor.

Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. The previous studies demonstrated that the endocannabinoid system played important roles in modulating several physiological functions such as sleep, olfaction, emotion, learning and memory, and reward behaviors. Mouse VD-hemopressin (α) [(m)VD-HPα], an 11-residue peptide derived from the α1 chain of hemoglobin, was recently presumed as a selective agonist of the CB1 receptor. The present study was undertaken to investigate the effects of (m)VD-HPα on the sleep-wake cycle and power spectrum of cortical EEG in freely moving rats and the potential neurons in the brain activated by (m)VD-HPα. The results showed that 20.1 nmol of (m)VD-HPα i.c.v. administration increased non-rapid eye movement (NREM) sleep in the first 2 h section accompanied by an increase in EEG delta (0.5-4 Hz) activity. The (m)VD-HPα-induced NREM sleep enhancement was due to extended episode duration instead of the episode number. In addition, the effect of (m)VD-HPα (20.1 nmol) on sleep-wake states was significantly attenuated by an antagonist of the CB1 receptor, AM251 (20 nmol, i.c.v.) but not by the CB2 receptor antagonist, AM630 (20 nmol, i.c.v.). In comparison with vehicle, (m)VD-HPα increased Fos-immunoreactive (-ir) neurons in the ventrolateral preoptic nucleus (VLPO), but reduced Fos-ir neurons in the lateral hypothalamus (LH), tuberomammillary nucleus (TMN), and locus coeruleus (LC). These findings suggest that (m)VD-HPα promotes NREM sleep via the CB1 cannabinoid receptor to probably activate VLPO GABAergic neurons, but inactivates the LH orexinergic, LC noradrenergic, and TMN histaminergic neurons.

Dupilumab for treatment of severe atopic dermatitis accompanied by lichenoid amyloidosis in adults: Two case reports.

BACKGROUND: Lichenoid amyloidosis (LA) is a subtype of primary cutaneous amyloidosis characterized by persistent multiple groups of hyperkeratotic papules, usually on the lower leg, back, forearm, or thigh. LA may be associated with several skin diseases, including atopic dermatitis (AD). The treatment of LA is considered to be difficult. However, as there is some overlap in the etiopathogenesis of LA and AD, AD treatment may also be effective for LA. CASE SUMMARY: Case 1: A 70-year-old man was diagnosed with severe AD with LA based on large dark erythema and papules on the trunk and buttocks and dense hemispherical millet-shaped papules with pruritus on the extensor side of the lower limbs. He had a long history of the disease (8 years), with repeated and polymorphic skin lesions. Given the poor efficacy of traditional treatments, this patient was recommended to receive dupilumab treatment. At the initial stage, 300 mg was injected subcutaneously every 2 wk. After 28 wk, the drug interval was extended to 1 mo due to the pandemic. Follow-up observations revealed that the patient reached an Eczema Area Severity Index of 90 (skin lesions improved by 90% compared with the baseline) by the end of the study. Moreover, Investigator's Global Assessment score was 1, and scoring atopic dermatitis index and numeric rating scale improved by 97.7% and 87.5% compared with the baseline, respectively, with LA skin lesions having largely subsided. Case 2: A 30-year-old woman was diagnosed with severe AD with LA, due to dense and substantial papules on the dorsal hands similar to changes in cutaneous amyloidosis, and erythema and papules scattered on limbs and trunk with pruritus, present for 25 years. After 16 wk of dupilumab treatment, she stopped, and skin lesions completely subsided, without recurrence since the last follow-up. CONCLUSION: Dupilumab shows rational efficacy and safety in the treatment of severe AD with LA, in addition to benefits in the quality of life of the patients.

Design, synthesis, and evaluation of N-methyl-propargylamine derivates as isoform-selective monoamine oxidases inhibitors for the treatment of nervous system diseases.

A novel series of N-methyl-propargylamine derivates were designed, synthesized, and evaluated as isoform-selective monoamine oxidases (MAO) inhibitors for the treatment of nervous system diseases. The in vitro studies showed some of the compounds exhibited considerable MAO-A selective inhibitory activity (IC50 of 14.86-17.16 nM), while some of the others exhibited great MAO-B selective inhibitory activity (IC50 of 4.37-17.00 nM). Further studies revealed that compounds A2 （IC50 against MAO-A: 17.16 ± 1.17 nM） and A5 (IC50 against MAO-B: 17.00 ± 1.10 nM) had significant abilities to protect PC12 cells from H2O2-induced apoptosis and reactive oxygen species (ROS) production. The parallel artificial membrane permeability assay showed A2 and A5 would be potent to cross the blood-brain barrier. The results indicated that A2 showed potential use in the therapy of MAO-A related diseases, such as depression and anxiety; while A5 exhibited promising ability in the treatment of MAO-B related diseases, such as Alzheimer's disease and Parkinson's disease.

Advanced lung adenocarcinoma (LUAD) patient with EGFR mutations benefited from multiline combination targeted therapies after osimertinib (AZD9291) resistance: a case report.

Background: The resistance mechanisms to osimertinib encompass on-target molecular alterations, such as the well-known epidermal growth factor receptor (EGFR) C797S resistance mutation, and off-target molecular alterations, such as the high-frequency MET amplification, but there's no further clear-cut therapeutic option to date for these individuals yet. Here we reported a lung adenocarcinoma (LUAD) patient who progressed on osimertinib benefited from multiline combination target-therapy and obtained a long-term progression-free survival (PFS). Case Description: A 70-year-old Chinese woman without a smoking history presented with stage IV advanced LUAD harboring EGFR 19del and then developed EGFR T790M mutation after 6-month treatment of gefitinib [a first-generation EGFR tyrosine kinase inhibitor (TKI)]. Osimertinib (a third-generation EGFR TKI) was immediately initiated, and the PFS was 11 months. After disease progression, next-generation sequencing (NGS) identified MET amplification, in addition to EGFR 19del. Combination therapy of osimertinib and cabozantinib (a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2)/capmatinib (a MET inhibitor) was administrated to the patient and the best overall response (OR) was stable disease (SD) with the PFS of 10 months. NGS detected the emergence of novel mutations EGFR S784Y and EGFR L799Q, together with EGFR C797S and all in cis with EGFR T790M, and retention of EGFR 19 del. The patient received pemetrexed (a chemotherapy drug) and bevacizumab (a VEGFR inhibitor) and achieved a partial response (PR). After 6 months of PFS, combination therapy of brigatinib (an inhibitor of ALK and EGFR) and cetuximab (an EGFR inhibitor) was initiated and the patient achieved a long-term PFS of 18 months and SD. Her overall survival (OS) was 51 months. Conclusions: This case highlights the importance of NGS on repeated biopsy which could offer better treatment options.

Unilateral lichen planus with Blaschko line distribution: A case report.

BACKGROUND: Lichen planus (LP) with distribution of lesions along Blaschko's lines is a rare entity, accounting for 0.24%-0.62% of all patients. Unilateral distribution of lesions in arm, leg, trunk, and waist is even less common. Approximately 10% of patients with LP manifest nail lesions. CASE SUMMARY: A 20-year-old woman presented to our department with polygonal, purpuric, flat-topped papules over the right arm, right leg, and right side of trunk and waist for the last 5 mo. The patient initially developed nail deformation in the left middle finger with no obvious cause, followed by development of blue-purple and red maculopapular rash with pruritus. During the disease course, the skin lesions aggravated and spread to several segments due to scratching. The lesions showed unilateral distribution along the Blaschko's lines. The diagnosis of LP along Blaschko's lines was established based on dermoscopy and skin biopsy. Her cutaneous lesions considerably improved after 4-wk treatment with intramuscular glucocorticoid, oral acitretin, topical glucocorticoid, and retinoids. CONCLUSION: Cases of LP involving multiple segments of the body along the Blaschko's lines with nail damage are rare.

Acute Lymphoblastic Leukemia in Combined Methylmalonic Acidemia and Homocysteinemia (cblC Type): A Case Report and Literature Review.

Background: Methylmalonic acidemia (MMA) can display many clinical manifestations, among which acute lymphoblastic leukemia (ALL) has not been reported, and congenital heart disease (CHD) is also rare. Case presentation: We report an MMA case with ALL and CHD in a 5.5-year-old girl. With developmental delay and local brain atrophy in MRI, she was diagnosed with cerebral palsy at 9 months old. Rehabilitation was performed since then. This time she was admitted to hospital because of weakness and widespread bleeding spots. ALL-L2 (pre-B-cell) was confirmed by bone marrow morphology and immunophenotyping. Echocardiography showed patent foramen ovale. The girl was treated with VDLD and CAML chemotherapy, during which she developed seizures, edema and renal insufficiency. Decrease of muscle strength was also found in physical examination. Screening for inherited metabolic disorders showed significantly elevated levels of methylmalonate-2, acetylcarnitine (C2), propionylcarnitine (C3), C3/C2 and homocysteine. Gene analysis revealed a compound heterozygous mutaion in MMACHC (NM_015,560): c.80A > G (p.Gln27Arg) and c.609G > A (p.Trp203*). CblC type MMA was diagnosed. Intramuscular injection of cyanocobalamin and intravenous L-carnitine treatment were applied. The edema vanished gradually, and chemotherapy of small dosage of vindesine was given intermittently when condition permitted. 2 months later, muscle strength of both lower limbs were significantly improved to nearly grade 5. The levels of methylmalonic acid and homocysteine were improved. Conclusion: Metabolic disease screening and gene analysis are very necessary for diseases with complex clinical symptoms. ALL can be a rare manifestation for MMA. Synopsis: We report a case of methylmalonic acidemia with acute lymphoblastic leukemia and congenital heart disease, which uncovered the importance of genetic testing and metabolic diseases screening in patients with multiple systemic organ involvement.

Biotin-streptavidin sandwich integrated PDA-ZnO@Au nanocomposite based SPR sensor for hIgG detection.

SPR is a mature optical biosensor technology for detecting biomolecular interactions without fluorescence or enzyme labeling. In this paper, we acquire a sensitive SPR biosensor based on ZnO@Au nanomaterial, and the classical sandwich strategy using biotin-streptavidin for secondary signal amplification system was used to detect human IgG (hIgG). Nano-zinc oxide (ZnO) has the dual characteristics of nanocomposite and traditional zinc oxide, with large specific surface area and high chemical activity. Besides, the gold-coated ZnO nanocrystals improve the optical properties of ZnO and enlarge the loading capacity with better biocompatibility. Therefore, a sensing platform based on PDA-ZnO@Au nanomaterial was constructed on gold film modified with mercaptan. Meanwhile, the biotin-avidin system in SPR sensor field has been rapidly developed and applied. Due to the highly selection of streptavidin (SA) and biotin interact with each other, GNRs-SA-biotin-Ab2 (GSAB-Ab2) were constructed to obtain the secondary enhancement of SPR signal. The influences of experimental conditions were also discussed. With optimal experimental conditions, introducing GSAB-Ab2 conjugate combined with a sandwich format, the resulting SPR biosensor provides a favourable range for hIgG determination of 0.0375-40 µg mL-1. The minimum detection concentration of hIgG that can be obtained by this method is approximately 67-fold lower than the conventional SPR sensor based on gold film. The sensitivity of SPR biosensor is significantly improved in a certain range.

PLK1 depletion alters homologous recombination and synaptonemal complex disassembly events during mammalian spermatogenesis.

Homologous recombination (HR) is an essential meiotic process that contributes to the genetic variation of offspring and ensures accurate chromosome segregation. Recombination is facilitated by the formation and repair of programmed DNA double-strand breaks. These DNA breaks are repaired via recombination between maternal and paternal homologous chromosomes and a subset result in the formation of crossovers. HR and crossover formation is facilitated by synapsis of homologous chromosomes by a proteinaceous scaffold structure known as the synaptonemal complex (SC). Recent studies in yeast and worms have indicated that polo-like kinases (PLKs) regulate several events during meiosis, including DNA recombination and SC dynamics. Mammals express four active PLKs (PLK1-4), and our previous work assessing localization and kinase function in mouse spermatocytes suggested that PLK1 coordinates nuclear events during meiotic prophase. Therefore, we conditionally mutated Plk1 in early prophase spermatocytes and assessed stages of HR, crossover formation, and SC processes. Plk1 mutation resulted in increased RPA foci and reduced RAD51/DMC1 foci during zygonema, and an increase of both class I and class II crossover events. Furthermore, the disassembly of SC lateral elements was aberrant. Our results highlight the importance of PLK1 in regulating HR and SC disassembly during spermatogenesis.

A Ti3C2-MXene-functionalized LRSPR biosensor based on sandwich amplification for human IgG detection.

Long-range surface plasmon resonance (LRSPR) has demonstrated excellent performance in sensing and detection, due to its higher accuracy and sensitivity compared with conventional surface plasmon resonance (cSPR). In this work, we establish an LRSPR biosensor which employs PDA/Ti3C2-MXene/PDA-gold film as a sensing substrate and gold nanoparticles (AuNPs) as enhancers. Ti3C2-MXene is an emerging two-dimensional (2D) layered material which is used extensively in immunoassay and biosensing. The sensing substrate comprises two polydopamine (PDA) films between which is sandwiched a Ti3C2-MXene film based on a gold film, which provides a large surface area and abundant binding sites to rabbit anti-human IgG (Ab1). Sandwich amplification is adopted to enhance the sensitivity of the LRSPR biosensor, and AuNPs/staphylococcal protein A (SPA)/mouse anti-human IgG (Ab2) composites are introduced into the flow cell as enhancers after the immune binding of human IgG to Ab1. The antigen (human IgG) detection range is 0.075 µg mL-1 to 40 µg mL-1, and the limit of detection is almost 20 times lower than that for cSPR biosensors. This novel LRSPR biosensor demonstrates excellent performance in immune sensing over a broad detection range and a low limit of detection. Subsequent modification of the LRSPR sensing platform could be made for extensive application in various biological detection fields.

The TBX1/miR-193a-3p/TGF-ß2 Axis Mediates CHD by Promoting Ferroptosis.

Congenital heart disease (CHD) is the most common noninfectious cause of death during the neonatal stage. T-box transcription factor 1 (TBX1) is the main genetic determinant of 22q11.2 deletion syndrome (22q11.2DS), which is a common cause of CHD. Moreover, ferroptosis is a newly discovered kind of programmed cell death. In this study, the interaction among TBX1, miR-193a-3p, and TGF-ß2 was tested using quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, and dual-luciferase reporter assays. TBX1 silencing was found to promote TGF-ß2 messenger ribonucleic acid (mRNA) and protein expression by downregulating the miR-193a-3p levels in H9c2 cells. In addition, the TBX1/miR-193a-3p/TGF-ß2 axis was found to promote ferroptosis based on assessments of lipid reactive oxygen species (ROS) levels, Fe2+ concentrations, mitochondrial ROS levels, and malondialdehyde (MDA) contents; Cell Counting Kit-8 (CCK-8) assays and transmission electron microscopy; and Western blotting analysis of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), NADPH oxidase 4 (NOX4), and acyl-CoA synthase long-chain family member 4 (ACSL4) protein expression. The protein expression of NRF2, GPX4, HO-1, NOX4, and ACSL4 and the level of MDA in human CHD specimens were also detected. In addition, TBX1 and miR-193a-3p expression was significantly downregulated and TGF-ß2 levels were high in human embryonic CHD tissues, as indicated by the H9c2 cell experiments. In summary, the TBX1/miR-193a-3p/TGF-ß2 axis mediates CHD by inducing ferroptosis in cardiomyocytes. TGF-ß2 may be a target gene for CHD diagnosis and treatment in children.

Overlapping roles for PLK1 and Aurora A during meiotic centrosome biogenesis in mouse spermatocytes.

The establishment of bipolar spindles during meiotic divisions ensures faithful chromosome segregation to prevent gamete aneuploidy. We analyzed centriole duplication, as well as centrosome maturation and separation during meiosis I and II using mouse spermatocytes. The first round of centriole duplication occurs during early prophase I, and then, centrosomes mature and begin to separate by the end of prophase I to prime formation of bipolar metaphase I spindles. The second round of centriole duplication occurs at late anaphase I, and subsequently, centrosome separation coordinates bipolar segregation of sister chromatids during meiosis II. Using a germ cell-specific conditional knockout strategy, we show that Polo-like kinase 1 and Aurora A kinase are required for centrosome maturation and separation prior to metaphase I, leading to the formation of bipolar metaphase I spindles. Furthermore, we show that PLK1 is required to block the second round of centriole duplication and maturation until anaphase I. Our findings emphasize the importance of maintaining strict spatiotemporal control of cell cycle kinases during meiosis to ensure proficient centrosome biogenesis and, thus, accurate chromosome segregation during spermatogenesis.

A Chiral-Label-Free SERS Strategy for the Synchronous Chiral Discrimination and Identification of Small Aromatic Molecules.

A versatile and robust chiral discrimination strategy for small aromatic compounds is of significant importance in multidisciplinary fields. However, most current methods lack either the sufficient sensitivity for recognizing the chirality of the target molecules or their molecular specificity information. We have developed a versatile and chiral-label-free surface-enhanced Raman scattering (SERS)-based chiral discrimination sensing system for small aromatic molecules, where the molecular structural specificity and enantioselectivity can be given synchronously in a single SERS spectrum. More than 10 types of chiral aromatic molecules were successfully identified by using this system. This work has enormous potential for recognizing chiral products effectively in sophisticated systems, especially in the fields of chiral synthesis and chiral catalysis.

Nitrogen Doped γ-Graphyne: A Novel Anode for High-Capacity Rechargeable Alkali-Ion Batteries.

High energy density is the major demand for next-generation rechargeable batteries, while the intrinsic low alkali metal adsorption of traditional carbon-based electrode remains the main challenge. Here, the mechanochemical route is proposed to prepare nitrogen doped γ-graphyne (NGY) and its high capacity is demonstrated in lithium (LIBs)/sodium (SIBs) ion batteries. The sample delivers large reversible Li (1037 mAh g-1 ) and Na (570.4 mAh g-1 ) storage capacities at 100 mA g-1 and presents excellent rate capabilities (526 mAh g-1 for LIBs and 180.2 mAh g-1 for SIBs) at 5 A g-1 . The superior Li/Na storage mechanisms of NGY are revealed by its 2D morphology evolution, quantitative kinetics, and theoretical calculations. The effects on the diffusion barriers (Eb ) and adsorption energies (Ead ) of Li/Na atoms in NGY are also studied and imine-N is demonstrated to be the ideal doping format to enhance the Li/Na storage performance. Besides, the Li/Na adsorption routes in NGY are optimized according to the experimental and the first-principles calculation results. This work provides a facile way to fabricate high capacity electrodes in LIBs/SIBs, which is also instructive for the design of other heteroatomic doped electrodes.