Effect of High-Sucrose Diet on the Occurrence and Progression of Diabetic Retinopathy and Dietary Modification Strategies.

As the most serious of the many worse new pathological changes caused by diabetes, there are many risk factors for the occurrence and development of diabetic retinopathy (DR). They mainly include hyperglycemia, hypertension, hyperlipidemia and so on. Among them, hyperglycemia is the most critical cause, and plays a vital role in the pathological changes of DR. High-sucrose diets (HSDs) lead to elevated blood glucose levels in vivo, which, through oxidative stress, inflammation, the production of advanced glycation end products (AGEs) and vascular endothelial growth factor (VEGF), cause plenty of pathological damages to the retina and ultimately bring about loss of vision. The existing therapies for DR primarily target the terminal stage of the disease, when irreversible visual impairment has appeared. Therefore, early prevention is particularly critical. The early prevention of DR-related vision loss requires adjustments to dietary habits, mainly by reducing sugar intake. This article primarily discusses the risk factors, pathophysiological processes and molecular mechanisms associated with the development of DR caused by HSDs. It aims to raise awareness of the crucial role of diet in the occurrence and progression of DR, promote timely changes in dietary habits, prevent vision loss and improve the quality of life. The aim is to make people aware of the importance of diet in the occurrence and progression of DR. According to the dietary modification strategies that we give, patients can change their poor eating habits in a timely manner to avoid theoretically avoidable retinopathy and obtain an excellent prognosis.

Infertility risk assessment with ultrasound in congenital adrenal hyperplasia male patients.

Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (rs = - 0.83, P < 0.001) and progressive motility (rs = - 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.

IL-37 ameliorates myocardial fibrosis by regulating mtDNA-enriched vesicle release in diabetic cardiomyopathy mice.

BACKGROUND: Diabetic cardiomyopathy (DCM), a serious complication of diabetes, leads to structural and functional abnormalities of the heart and ultimately evolves to heart failure. IL-37 exerts a substantial influence on the regulation of inflammation and metabolism. Whether IL-37 is involved in DCM is unknown. METHODS: The plasma samples were collected from healthy controls, diabetic patients and DCM patients, and the level of IL-37 and its relationship with heart function were observed. The changes in cardiac function, myocardial fibrosis and mitochondrial injury in DCM mice with or without IL-37 intervention were investigated in vivo. By an in vitro co-culture approach involving HG challenge of cardiomyocytes and fibroblasts, the interaction carried out by cardiomyocytes on fibroblast profibrotic activation was studied. Finally, the possible interactive mediator between cardiomyocytes and fibroblasts was explored, and the intervention role of IL-37 and its relevant molecular mechanisms. RESULTS: We showed that the level of plasma IL-37 in DCM patients was upregulated compared to that in healthy controls and diabetic patients. Both recombinant IL-37 administration or inducing IL-37 expression alleviated cardiac dysfunction and myocardial fibrosis in DCM mice. Mechanically, hyperglycemia impaired mitochondria through SIRT1/AMPK/PGC1α signaling, resulting in significant cardiomyocyte apoptosis and the release of extracellular vesicles containing mtDNA. Fibroblasts then engulfed these mtDNA-enriched vesicles, thereby activating TLR9 signaling and the cGAS-STING pathway to initiate pro-fibrotic process and adverse remodeling. However, the presence of IL-37 ameliorated mitochondrial injury by preserving the activity of SIRT1-AMPK-PGC1α axis, resulting in a reduction in release of mtDNA-enriched vesicle and ultimately attenuating the progression of DCM. CONCLUSIONS: Collectively, our study demonstrates a protective role of IL-37 in DCM, offering a promising therapeutic agent for this disease.

Phospholipid Type Regulates Protein Corona Composition and In Vivo Performance of Lipid Nanodiscs.

Over the years, there has been significant interest in PEGylated lipid-based nanocarriers within the drug delivery field. The inevitable interplay between the nanocarriers and plasma protein plays a pivotal role in their in vivo biological fate. Understanding the factors influencing lipid-based nanocarrier and protein corona interactions is of paramount importance in the design and clinical translation of these nanocarriers. Herein, discoid-shaped lipid nanodiscs (sNDs) composed of different phospholipids with varied lipid tails and head groups were fabricated. We investigated the impact of phospholipid components on the interaction between sNDs and serum proteins, particle stability, and biodistribution. The results showed that all of these lipid nanodiscs remained stable over a 15 day storage period, while their stability in the blood serum demonstrated significant differences. The sND composed of POPG exhibited the least stability due to its potent complement activation capability, resulting in rapid blood clearance. Furthermore, a negative correlation between the complement activation capability and serum stability was identified. Pharmacokinetic and biodistribution experiments indicated that phospholipid composition did not influence the capability of sNDs to evade the accelerated blood clearance phenomenon. Complement deposition on the sND was inversely associated with the area under the curve. Additionally, all lipid nanodiscs exhibited dominant adsorption of apolipoprotein. Remarkably, the POPC-based lipid nanodisc displayed a significantly higher deposition of apolipoprotein E, contributing to an obvious brain distribution, which provides a promising tool for brain-targeted drug delivery.

Human Airway Organoids and Multimodal Imaging-Based Toxicity Evaluation of 1-Nitropyrene.

Despite significant advances in understanding the general health impacts of air pollution, the toxic effects of air pollution on cells in the human respiratory tract are still elusive. A robust, biologically relevant in vitro model for recapitulating the physiological response of the human airway is needed to obtain a thorough understanding of the molecular mechanisms of air pollutants. In this study, by using 1-nitropyrene (1-NP) as a proof-of-concept, we demonstrate the effectiveness and reliability of evaluating environmental pollutants in physiologically active human airway organoids. Multimodal imaging tools, including live cell imaging, fluorescence microscopy, and MALDI-mass spectrometry imaging (MSI), were implemented to evaluate the cytotoxicity of 1-NP for airway organoids. In addition, lipidomic alterations upon 1-NP treatment were quantitatively analyzed by nontargeted lipidomics. 1-NP exposure was found to be associated with the overproduction of reactive oxygen species (ROS), and dysregulation of lipid pathways, including the SM-Cer conversion, as well as cardiolipin in our organoids. Compared with that of cell lines, a higher tolerance of 1-NP toxicity was observed in the human airway organoids, which might reflect a more physiologically relevant response in the native airway epithelium. Collectively, we have established a novel system for evaluating and investigating molecular mechanisms of environmental pollutants in the human airways via the combinatory use of human airway organoids, multimodal imaging analysis, and MS-based analyses.

Mage transposon: a novel gene delivery system for mammalian cells.

Transposons, as non-viral integration vectors, provide a secure and efficient method for stable gene delivery. In this study, we have discovered Mage (MG), a novel member of the piggyBac(PB) family, which exhibits strong transposability in a variety of mammalian cells and primary T cells. The wild-type MG showed a weaker insertion preference for near genes, transcription start sites (TSS), CpG islands, and DNaseI hypersensitive sites in comparison to PB, approaching the random insertion pattern. Utilizing in silico virtual screening and feasible combinatorial mutagenesis in vitro, we effectively produced the hyperactive MG transposase (hyMagease). This variant boasts a transposition rate 60% greater than its native counterpart without significantly altering its insertion pattern. Furthermore, we applied the hyMagease to efficiently deliver chimeric antigen receptor (CAR) into T cells, leading to stable high-level expression and inducing significant anti-tumor effects both in vitro and in xenograft mice models. These findings provide a compelling tool for gene transfer research, emphasizing its potential and prospects in the domains of genetic engineering and gene therapy.

In Operando Monitoring the Stress Evolution of Silicon Anode Electrodes during Battery Operation via Optical Fiber Sensors.

Silicon (Si) anode has attracted broad attention because of its high theoretical specific capacity and low working potential. However, the severe volumetric changes of Si particles during the lithiation process cause expansion and contraction of the electrodes, which induces a repeatedly repair of solid electrolyte interphase, resulting in an excessive consuming of electrolyte and rapid capacity decay. Clearly known the deformation and stress changing at µÎµ resolution in the Si-based electrode during battery operation provides invaluable information for the battery research and development. Here, an in operando approach is developed to monitor the stress evolution of Si anode electrodes via optical fiber Bragg grating (FBG) sensors. By implanting FBG sensor at specific locations in the pouch cells with different Si anodes, the stress evolution of Si electrodes has been systematically investigated, and Δσ/areal capacity is proposed for stress assessment. The results indicate that the differences in stress evolution are nested in the morphological changes of Si particles and the evolution characteristics of electrode structures. The proposed technique provides a brand-new view for understanding the electrochemical mechanics of Si electrodes during battery operation.

B Cells Dynamic in Aging and the Implications of Nutritional Regulation.

Aging negatively affects B cell production, resulting in a decrease in B-1 and B-2 cells and impaired antibody responses. Age-related B cell subsets contribute to inflammation. Investigating age-related alterations in the B-cell pool and developing targeted therapies are crucial for combating autoimmune diseases in the elderly. Additionally, optimal nutrition, including carbohydrates, amino acids, vitamins, and especially lipids, play a vital role in supporting immune function and mitigating the age-related decline in B cell activity. Research on the influence of lipids on B cells shows promise for improving autoimmune diseases. Understanding the aging B-cell pool and considering nutritional interventions can inform strategies for promoting healthy aging and reducing the age-related disease burden.

Reexamining the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin.

Higher drug loading employed in nanoscale delivery platforms is a goal that researchers have long sought after. But such viewpoint remains controversial because the impacts that nanocarriers bring about on bodies have been seriously overlooked. In the present study we investigated the effects of drug loading on the in vivo performance of PEGylated liposomal doxorubicin (PLD). We prepared PLDs with two different drug loading rates: high drug loading rate, H-Dox, 12.9% w/w Dox/HSPC; low drug loading rate, L-Dox, 2.4% w/w Dox/HSPC (L-Dox had about 5 folds drug carriers of H-Dox at the same Dox dose). The pharmaceutical properties and biological effects of H-Dox and L-Dox were compared in mice, rats or 4T1 subcutaneous tumor-bearing mice. We showed that the lowering of doxorubicin loading did not cause substantial shifts to the pharmaceutical properties of PLDs such as in vitro and in vivo stability (stable), anti-tumor effect (equivalent effective), as well as tissue and cellular distribution. Moreover, it was even more beneficial for mitigating the undesired biological effects caused by PLDs, through prolonging blood circulation and alleviating cutaneous accumulation in the presence of pre-existing anti-PEG Abs due to less opsonins (e.g. IgM and C3) deposition on per particle. Our results warn that the effects of drug loading would be much more convoluted than expected due to the complex intermediation between nanocarriers and bodies, urging independent investigation for each individual delivery platform to facilitate clinical translation and application.

High-Speed Automated Reconstruction of Drosophila Larval Brain from Volumetric EM Data.

To uncover the relationship between neural activity and behavior, it is essential to reconstruct neural circuits. However, methods typically used for neuron reconstruction from volumetric electron microscopy (EM) dataset are often time-consuming and require extensive manual proofreading, making it difficult to reproduce in a typical laboratory setting. To address this challenge, we have developed a set of acceleration techniques that build upon the Flood Filling Network (FFN), significantly reducing the time required for this task. These techniques can be easily adapted to other similar datasets and laboratory settings. To validate our approach, we tested our pipeline on a dataset of Drosophila larval brain serial section EM images at synaptic-resolution level. Our results demonstrate that our pipeline significantly reduces the inference time compared to the FFN baseline method and greatly reduces the time required for reconstructing the 3D morphology of neurons.

ACMSD mediated de novo NAD+ biosynthetic impairment in cardiac endothelial cells as a potential therapeutic target for diabetic cardiomyopathy.

OBJECT: The highly conserved α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) is the key enzyme that regulates the de novo NAD+ synthesis from tryptophan. NAD+ metabolism in diabetic cardiomyopathy (DCM) was not elucidated yet. METHODS: Mice were assigned to non-diabetic (NDM) group, streptozocin (STZ)-induced diabetic (DM) group, and nicotinamide (NAM) treated (DM + NAM) group. ACMSD mediated NAD+ metabolism were studied both in mice and patients with diabetes. RESULTS: NAD+ level was significantly lower in the heart of DM mice than that of the NDM group. Supplementation with NAM could partially increased myocardial capillary density and ameliorated myocardial fibrosis by increasing NAD+ level through salvage pathway. Compared with NDM mice, the expression of ACMSD in myocardial endothelial cells of DM mice was significantly increased. It was further confirmed that in endothelial cells, high glucose promoted the expression of ACMSD. Inhibition of ACMSD could increase de novo NAD+ synthesis and improve endothelial cell function by increasing Sirt1 activity. Targeted mass spectrometry analysis indicated increased ACMSD enzyme activity in diabetic patients, higher ACMSD activity increased risk of heart diastolic dysfunction. CONCLUSION: In summary, increased expression of ACMSD lead to impaired de novo NAD+ synthesis in diabetic heart. Inhibition of ACMSD could potentially improve DCM.

Jia-Wei-Kai-Xin-San Treatment Alleviated Mild Cognitive Impairment through Anti-Inflammatory and Antiapoptotic Mechanisms in SAMP8 Mice.

Background: Alleviating mild cognitive impairment (MCI) is crucial to delay the progression of Alzheimer's disease (AD). Jia-Wei-Kai-Xin-San (JWKXS) is applied for treating AD with MCI. However, the mechanism of JWKXS in the treatment of MCI is unclear. Thus, this study aimed to investigate the effect and mechanism of JWKXS in SAMP8 mice models of MCI. Methods: MCI models were established to examine learning and memory ability and explore the pathomechanisms in brain of SAMP8 mice at 4, 6, and 8 months. The mice were treated for 8 weeks and the effects of JWKXS on MCI were characterized through Morris water maze and HE/Nissl's/immunohistochemical staining. Its mechanism was predicted by the combination of UPLC-Q-TOF/MS and system pharmacology analysis, further verified with SAMP8 mice, BV2 microglial cells, and PC12 cells. Results: It was found that 4-month-old SAMP8 mice exhibited MCI. Two months of JWKXS treatment improved the learning and memory ability, alleviated the hippocampal tissue and neuron damage. Through network pharmacology, four key signaling pathways were found to be involved in treatment of MCI by JWKXS, including TLR4/NF-κB pathway, NLRP3 inflammasome activation, and intrinsic and extrinsic apoptosis. In vitro and in vivo experiments demonstrated that JWKXS attenuated neuroinflammation by inhibiting microglia activation, suppressing TLR4/NF-κB and NLRP3 inflammasome pathways, and blocking the extrinsic and intrinsic apoptotic pathways leading to neuronal apoptosis suppression in the hippocampus. Conclusion: JWKXS treatment improved the learning and memory ability and conferred neuroprotective effects against MCI by inducing anti-inflammation and antiapoptosis. Limitations. The small sample size and short duration of the intervention limit in-depth investigation of the mechanisms. Future Prospects. This provides a direction for further clarification of the anti-AD mechanism, and provides certain data support for the formulation to move toward clinical practice.

The genome of the deep-sea anemone Actinernus sp. contains a mega-array of ANTP-class homeobox genes.

Members of the phylum Cnidaria include sea anemones, corals and jellyfish, and have successfully colonized both marine and freshwater habitats throughout the world. The understanding of how cnidarians adapt to extreme environments such as the dark, high-pressure deep-sea habitat has been hindered by the lack of genomic information. Here, we report the first chromosome-level deep-sea cnidarian genome, of the anemone Actinernus sp., which was 1.39 Gbp in length and contained 44 970 gene models including 14 806 tRNA genes and 30 164 protein-coding genes. Analyses of homeobox genes revealed the longest chromosome hosts a mega-array of Hox cluster, HoxL, NK cluster and NKL homeobox genes; until now, such an array has only been hypothesized to have existed in ancient ancestral genomes. In addition to this striking arrangement of homeobox genes, analyses of microRNAs revealed cnidarian-specific complements that are distinctive for nested clades of these animals, presumably reflecting the progressive evolution of the gene regulatory networks in which they are embedded. Also, compared with other sea anemones, circadian rhythm genes were lost in Actinernus sp., which likely reflects adaptation to living in the dark. This high-quality genome of a deep-sea cnidarian thus reveals some of the likely molecular adaptations of this ecologically important group of metazoans to the extreme deep-sea environment. It also deepens our understanding of the evolution of genome content and organization of animals in general and cnidarians in particular, specifically from the viewpoint of key developmental control genes like the homeobox-encoding genes, where we find an array of genes that until now has only been hypothesized to have existed in the ancient ancestor that pre-dated both the cnidarians and bilaterians.

Protein corona on brain targeted nanocarriers: Challenges and prospects.

Safe and efficient medical therapy for brain diseases is still an unmet clinical need due to various barriers represented by the blood-brain barrier. Well-designed brain targeted nanocarriers are potential solutions for enhanced brain drug delivery; however, the complicated in vivo process attenuates performance of nanocarriers, which severely hampers clinical translation. The formation of protein corona (PC) is inevitable for nanocarriers circulation and transport in biofluids, acting as an important factor to regulate in vivo performance of nanocarriers. In this review, the reported strategies have been retrospected for better understanding current situation in developing brain targeted nanocarriers. The interplay between brain targeted nanocarriers and plasma proteins is emphasized to comprehend how the nanocarriers adsorb proteins by certain synthetic identity, and following regulations on in vivo performance of nanocarriers. More importantly, the mainstream methods to promote efficiency of nanocarriers by regulating PC, defined as in vitro functionalization and in vivo functionalization strategies, are also discussed. Finally, viewpoints about future development of brain targeted nanocarriers according to the understanding on nanocarriers-PC interaction are proposed.

First principles insights into the interaction mechanism of iron doped thermally activated kaolinite with Cd and Pb pollutants in organic solid waste incineration flue gas.

Incineration of organic solid wastes is accompanied by the heavy metal emission through flue gas. As an inexpensive and efficient heavy metal adsorbent, the improvement of kaolinite adsorption performance for heavy metals has drawn widespread interests. In this work, the interaction mechanisms between various kaolinite surfaces and Cd/Pb species are explored through first principles calculations. The results show that the combination of Fe doping and dehydroxylation enhances the activity of kaolinite surfaces, analysis of adsorption configurations reveal that both Cd and Pb species are immobilized through chemisorption on the -H + Fe surface. At the microscopic level, further electronic structure analysis shows that the composite modified kaolinite surface has more electron transfer and more pronounced orbital hybridization and overlap compared to the original kaolinite surface, demonstrating that the modification means of dehydroxylation and Fe doping indeed enhanced the activity of the kaolinite surface, especially the activity of the O atoms in the vicinity of the Fe atom and that the O atoms are more efficiently bonded as ionic connecting Cd/Pb species for the purpose of trapping Cd/Pb species. This study points out the research direction and provides basic theoretical support for the development of new kaolinite adsorbents in the future.

Integration of Metabolome and Transcriptome Reveals the Major Metabolic Pathways and Potential Biomarkers in Response to Freeze-Stress Regulation in Apple (Malus domestica).

Freezing stress is the main factor affecting the normal growth and distribution of plants. The safe overwintering of a perennial deciduous plant is a crucial link to ensuring its survival and yield. However, little is known about the molecular mechanism of its gene regulation metabolites as related to its freeze-tolerance. In order to enhance our comprehension of freeze-tolerance metabolites and gene expression in dormant apple trees, we examined the metabolic and transcriptomic differences between 'Ralls' and 'Fuji', two apple varieties with varying degrees of resistance to freezing. The results of the freezing treatment showed that 'Ralls' had stronger freeze-tolerance than 'Fuji'. We identified 302, 334, and 267 up-regulated differentially accumulated metabolites (DAMs) and 408, 387, and 497 down-regulated DAMs between 'Ralls' and 'Fuji' under -10, -15, and -20 °C treatment, respectively. A total of 359 shared metabolites were obtained in the upward trend modules, of which 62 metabolites were associated with 89 pathways. The number of up-regulated genes accounted for 50.2%, 45.6%, and 43.2% of the total number of differentially expressed genes (DEGs), respectively, at -10, -15, and -20 °C. Through combined transcriptome and metabolome analysis, we identified 12 pathways that included 16 DAMs and 65 DEGs. Meanwhile, we found that 20 DEGs were identified in the phenylpropanoid biosynthesis pathway and its related pathways, involving the metabolism of p-Coumaroyl-CoA, 7, 4'-Dihydroxyflavone, and scolymoside. These discoveries advance our comprehension of the molecular mechanism underlying apple freeze-tolerance and provide genetic material for breeding apple cultivars with enhanced freeze-tolerance.

Hematopoietic Stem Cell: Regulation and Nutritional Intervention.

Hematopoietic stem cells (HSCs) are crucial for the life maintenance of bio-organisms. However, the mechanism of HSC regulation is intricate. Studies have shown that there are various factors, either intrinsically or extrinsically, that shape the profile of HSCs. This review systematically summarizes the intrinsic factors (i.e., RNA-binding protein, modulators in epigenetics and enhancer-promotor-mediated transcription) that are reported to play a pivotal role in the function of HSCs, therapies for bone marrow transplantation, and the relationship between HSCs and autoimmune diseases. It also demonstrates the current studies on the effects of high-fat diets and nutrients (i.e., vitamins, amino acids, probiotics and prebiotics) on regulating HSCs, providing a deep insight into the future HSC research.

Apical-Out Human Airway Organoids Modeling SARS-CoV-2 Infection.

The respiratory epithelium, particularly the airway epithelium, is the primary infection site for respiratory pathogens. The apical surface of epithelial cells is constantly exposed to external stimuli including invading pathogens. Efforts have been made to establish organoid cultures to recapitulate the human respiratory tract. However, a robust and simple model with an easily accessible apical surface would benefit respiratory research. Here, we report the generation and characterization of apical-out airway organoids from the long-term expandable lung organoids that we previously established. The apical-out airway organoids morphologically and functionally recapitulated the human airway epithelium at a comparable level to the apical-in airway organoids. Moreover, apical-out airway organoids sustained productive and multicycle replication of SARS-CoV-2, and accurately recapitulated the higher infectivity and replicative fitness of the Omicron variants BA.5 and B.1.1.529 and an ancestral virus. In conclusion, we established a physiologically relevant and convenient apical-out airway organoid model for studying respiratory biology and diseases.

Establishing Bipotential Human Lung Organoid Culture System and Differentiation to Generate Mature Alveolar and Airway Organoids.

A robust in vitro model of the human respiratory epithelium, including the alveolar and the airway epithelium, is essential for understanding the biology and pathology of the human respiratory system. We previously described a protocol to derive human lung organoids from primary lung tissues. We now describe a protocol to induce bidirectional differentiation to generate mature alveolar or airway organoids. The lung organoids are consecutively expanded for over one year with high stability, while the differentiated alveolar and airway organoids morphologically and functionally simulate the human alveolar and airway epithelium to a near-physiological level. Thus, we establish a robust organoid culture system of the entire human respiratory epithelium, the first two-phase bipotential organoid culture system that enables long-term expansion and bidirectional differentiation of respiratory epithelial cells. The long-term expandable lung organoids and differentiated organoids generate a stable and renewable source of respiratory epithelial cells, enabling scientists to reconstruct and expand the human respiratory epithelium in culture dishes. The respiratory organoid system provides a unique and physiologically active in vitro model of the human respiratory epithelium for various applications, including studying respiratory viral infection, disease modeling, drug screening, and pre-clinical testing. Graphical abstract.

Human airway and nasal organoids reveal escalating replicative fitness of SARS-CoV-2 emerging variants.

The high transmissibility of SARS-CoV-2 Omicron subvariants was generally ascribed to immune escape. It remained unclear whether the emerging variants have gradually acquired replicative fitness in human respiratory epithelial cells. We sought to evaluate the replicative fitness of BA.5 and earlier variants in physiologically active respiratory organoids. BA.5 exhibited a dramatically increased replicative capacity and infectivity than B.1.1.529 and an ancestral strain wildtype (WT) in human nasal and airway organoids. BA.5 spike pseudovirus showed a significantly higher entry efficiency than that carrying WT or B.1.1.529 spike. Notably, we observed prominent syncytium formation in BA.5-infected nasal and airway organoids, albeit elusive in WT- and B.1.1.529-infected organoids. BA.5 spike-triggered syncytium formation was verified by lentiviral overexpression of spike in nasal organoids. Moreover, BA.5 replicated modestly in alveolar organoids, with a significantly lower titer than B.1.1.529 and WT. Collectively, the higher entry efficiency and fusogenic activity of BA.5 spike potentiated viral spread through syncytium formation in the human airway epithelium, leading to enhanced replicative fitness and immune evasion, whereas the attenuated replicative capacity of BA.5 in the alveolar organoids may account for its benign clinical manifestation.