Mechanical overloading can promote cartilage senescence and osteoarthritis (OA) development, but its impact on synovial macrophages and the interaction between macrophages and chondrocytes remain unknown. Here, we found that macrophages exhibited M1 polarization under mechanical overloading and secreted ectosomes that induced cartilage degradation and senescence. By performing miRNA sequencing on ectosomes, we identified highly expressed miR-350-3p as a key factor mediating the homeostatic imbalance of chondrocytes caused by M1-polarized macrophages, this result being confirmed by altering the miR-350-3p level in chondrocytes with mimics and inhibitor. In experimental OA mice, miR-350-3p was increased in synovium and cartilage, while intra-articular injection of antagomir-350-3p inhibited the increase of miR-350-3p and alleviated cartilage degeneration and senescence. Further studies showed that macrophage-derived ectosomal miR-350-3p promoted OA progression by inhibiting nuclear receptor binding SET domain protein 1(NSD1) in chondrocytes and regulating histone H3 lysine 36(H3K36) methylation. This study demonstrated that the targeting of macrophage-derived ectosomal miRNAs was a potential therapeutic method for mechanical overload-induced OA.
[This corrects the article DOI: 10.3389/fbioe.2024.1338901.].
Osteoarthritis (OA) has become a serious problem to the human society for years due to its high economic burden, disability, pain, and severe impact on the patient's lifestyle. The importance of current clinical imaging modalities in the assessment of the onset and progression of OA is well recognized by clinicians, but these modalities can only detect OA in the II stage with significant structural deterioration and clinical symptoms. Blood vessel formation induced by vascular endothelial growth factor (VEGF) occurs in the early stage and throughout the entire course of OA, enables VEGF relating gene sequence to act as a biomarker in the field of early diagnosis and monitoring of the disease. Here in, a facile rapid detection of VEGF relating ssDNA sequence was developed, in which manganese-based zeolitic imidazolate framework nanoparticles (Mn-ZIF-NPs) were synthesized by a simple coprecipitation strategy, followed by the introduction and surficial absorption of probe ssDNAs and the CRISPR/Cas12a system components. Furthermore, fluorescence experiments demonstrated that the biosensor displayed a low detection limit of 2.49 nM, a good linear response to the target ssDNA ranging from 10 nM to 500 nM, and the ability of distinguishing single nucleotide polymorphism. This finding opens a new window for the feasible and rapid detection of ssDNA molecules for the early diagnose of OA.
Tree peony (Paeonia suffruticosa) is a significant medicinal plant. However, the low rooting number is a bottleneck problem in the micropropagation protocols of P. ostii 'Fengdan'. The activity of superoxide dismutase (SOD) is closely related to root development. But research on the SOD gene's impact on rooting is still lacking. In this study, RNA sequencing (RNA-seq) was used to analyze the four crucial stages of root development in P. ostii 'Fengdan' seedlings, including the early root primordium formation stage (Gmfq), root primordium formation stage (Gmf), root protrusion stage (Gtq), and root outgrowth stage (Gzc). A total of 141.77 GB of data were obtained; 71,718, 29,804, and 24,712 differentially expressed genes (DEGs) were identified in the comparison groups of Gmfq vs. Gmf, Gmf vs. Gtq, and Gtq vs. Gzc, respectively. Among the 20 most highly expressed DEGs in the three comparison groups, only the CuZnSOD gene (SUB13202229, PoSOD) was found to be significantly expressed in Gtq vs. Gzc. The overexpression of PoSOD increased the number of adventitious roots and promoted the activities of peroxidase (POD) and SOD in P. ostii 'Fengdan'. The gene ADVENTITIOUS ROOTING RELATED OXYGENASE1 (PoARRO-1), which is closely associated with the development of adventitious roots, was also significantly upregulated in overexpressing PoSOD plants. Furthermore, PoSOD interacted with PoARRO-1 in yeast two-hybrid (Y2H) and biomolecular luminescence complementation (BiFC) assays. In conclusion, PoSOD could interact with PoARRO-1 and enhance the root development of tube plantlets in P. ostii 'Fengdan'. This study will help us to preliminarily understand the molecular mechanism of adventitious root formation and improve the root quality of tree peony and other medicinal plants.
Structure optimization based on natural products has become an effective way to develop new green fungicides. In this project, thirty-two novel NPs-derived hydrazide compounds were designed and synthesized by introducing the bioactive hydrazide substructure into sinapic acid and mycophenolic acid. The fungicidal bioassays indicated that the obtained hydrazide compounds showed excellent and selective fungicidal activity against specific pathogens, especially compounds C8, D7, and D8 with EC50 values of 0.63, 0.56, and 0.43 µg mL-1 against M. oryzae, respectively. SAR indicated that the introduction of 4-fluoro, 4-chloro, and 2,4-difluoro groups was conducive to improving the fungicidal activity, while the extension of the hydrazide bridge would affect the selectivity for inhibitory activity. Subsequently, the effects of hydrazide compounds on rice seedling and zebrafish growth were also investigated. The fungicidal mechanism implied that treatment with compound B4 would cause significant changes in metabolites of plasma membrane-related linolenic acid metabolism, arachidonic acid metabolism, and α-linolenic acid metabolism pathways, which further led to the wrinkled hyphae and the blurred plasma membrane and cytoplasm. Finally, the frontier molecular orbitals and charge distribution were calculated to analyze the differences in bioactivity from a structural perspective. These results provide important guidance for the development and practical application of novel fungicides.
Fungicides, Industrial , Animals , Fungicides, Industrial/pharmacology , Fungicides, Industrial/chemistry , Structure-Activity Relationship , Mycophenolic Acid/pharmacology , Zebrafish
BACKGROUND: High rates of vaccination and natural infection drive immunity and redirect selective viral adaptation. Updated boosters are installed to cope with drifted viruses, yet data on adaptive evolution under increasing immune pressure in a real-world situation are lacking. METHODS: Cross-sectional study to characterise SARS-CoV-2 mutational dynamics and selective adaptation over >1 year in relation to vaccine status, viral phylogenetics, and associated clinical and demographic variables. FINDINGS: The study of >5400 SARS-CoV-2 infections between July 2021 and August 2022 in metropolitan New York portrayed the evolutionary transition from Delta to Omicron BA.1-BA.5 variants. Booster vaccinations were implemented during the Delta wave, yet booster breakthrough infections and SARS-CoV-2 re-infections were almost exclusive to Omicron. In adjusted logistic regression analyses, BA.1, BA.2, and BA.5 had a significant growth advantage over co-occurring lineages in the boosted population, unlike BA.2.12.1 or BA.4. Selection pressure by booster shots translated into diffuse adaptive evolution in Delta spike, contrasting with strong, receptor-binding motif-focused adaptive evolution in BA.2-BA.5 spike (Fisher Exact tests; non-synonymous/synonymous mutation rates per site). Convergent evolution has become common in Omicron, engaging spike positions crucial for immune escape, receptor binding, or cleavage. INTERPRETATION: Booster shots are required to cope with gaps in immunity. Their discriminative immune pressure contributes to their effectiveness but also requires monitoring of selective viral adaptation processes. Omicron BA.2 and BA.5 had a selective advantage under booster vaccination pressure, contributing to the evolution of BA.2 and BA.5 sublineages and recombinant forms that predominate in 2023. FUNDING: The study was supported by NYU institutional funds and partly by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.
COVID-19 , Vaccines , Humans , SARS-CoV-2/genetics , COVID-19/epidemiology , COVID-19/prevention & control , Cross-Sectional Studies , Breakthrough Infections , Antibodies, Viral , Antibodies, Neutralizing
Inflammation of chondrocytes plays a critical role in the occurrence and development of osteoarthritis (OA). Recent evidence indicated exosomes derived from mesenchymal stem cells (MSCs-Exos) exhibit excellent anti-inflammatory ability in many troublesome inflammatory diseases including OA. In the present study, we aimed to explore the role of human umbilical cord-derived MSCs-Exos (hUC-MSCs-Exos) in treating the inflammation of chondrocytes and its related mechanisms. Ultracentrifugation was applied to isolate hUC-MSCs-Exos from the culture supernatant of hUC-MSCs. Two OA-like in vitro inflammation models of human articular chondrocytes induced with interleukin 1ß (IL-1ß) and co-incubation with macrophage utilizing transwell cell culture inserts were both used to evaluate the anti-inflammatory effects of hUC-MSCs-Exos. The mRNA sequencing of chondrocytes after treatment and microRNA (miRNA) sequencing of hUC-MSCs-Exos were detected and analyzed for possible mechanism analysis. The results of the study confirmed that hUC-MSCs-Exos had a reversed effect of IL-1ß on chondrocytes in the expression of collagen type II alpha 1 (COL2A1) and matrix metalloproteinase 13 (MMP13). The addition of hUC-MSCs-Exos to M1 macrophages in the upper chamber showed down-regulation of IL-1ß and tumor necrosis factor α (TNF-α), up-regulation of IL-10 and arginase1 (ARG1), and reversed the gene and protein expression of COL2A1 and MMP13 of the chondrocytes seeded in the lower chamber. The results of this study confirmed the anti-inflammatory effects of hUC-MSCs-Exos in the human articular chondrocytes inflammation model. hUC-MSCs-Exos may be used as a potential cell-free treatment strategy for chondrocyte inflammation in OA.
Membrane-type I metalloproteinase (MT1-MMP/MMP14) plays a key role in various pathophysiological processes, indicating an unaddressed need for a targeted therapeutic approach. However, mice genetically deficient in Mmp14 show severe defects in development and growth. To investigate the possibility of MT1-MMP inhibition as a safe treatment in adults, we generated global Mmp14 tamoxifen-induced conditional knockout (Mmp14kd) mice and found that MT1-MMP deficiency in adult mice resulted in severe inflammatory arthritis. Mmp14kd mice started to show noticeably swollen joints two weeks after tamoxifen administration, which progressed rapidly. Mmp14kd mice reached a humane endpoint 6 to 8 weeks after tamoxifen administration due to severe arthritis. Plasma TNF-α levels were also significantly increased in Mmp14kd mice. Detailed analysis revealed chondrocyte hypertrophy, synovial fibrosis, and subchondral bone remodeling in the joints of Mmp14kd mice. However, global conditional knockout of MT1-MMP in adult mice did not affect body weight, blood glucose, or plasma cholesterol and triglyceride levels. Furthermore, we observed substantial expression of MT1-MMP in the articular cartilage of patients with osteoarthritis. We then developed chondrocyte-specific Mmp14 tamoxifen-induced conditional knockout (Mmp14chkd) mice. Chondrocyte MT1-MMP deficiency in adult mice also caused apparent chondrocyte hypertrophy. However, Mmp14chkd mice did not exhibit synovial hyperplasia or noticeable arthritis, suggesting that chondrocyte MT1-MMP is not solely responsible for the onset of severe arthritis observed in Mmp14kd mice. Our findings also suggest that highly cell-type specific inhibition of MT1-MMP is required for its potential therapeutic use.
Cartilage, Articular , Osteoarthritis , Animals , Mice , Blood Glucose , Body Weight , Matrix Metalloproteinase 14/genetics , Osteoarthritis/chemically induced , Osteoarthritis/genetics
Because both Babesia microti and Borrelia burgdorferi can be transmitted by the bite of a single coinfected Ixodes scapularis tick, an attempt was made to determine the frequency with which whole blood samples that tested positive for B. microti infection by polymerase chain reaction (PCR) would also test positive by PCR for B. burgdorferi infection. Over a 7-year period from 2013 to 2019, 119 different patients tested positive for B. microti infection by PCR on at least one blood sample. Among the 118 patients with a positive B. microti PCR blood sample that could also be tested by a qualitative PCR for B. burgdorferi, only one patient tested positive (0.85%, 95% CI 0.02 to 4.6%). Routine PCR testing of every B. microti PCR-positive blood specimen to detect B. burgdorferi coinfection appears to have a low yield, even in a highly endemic geographic area for both of these infections.
Objectives: The aim of this study was to investigate the effectiveness of narrative therapy in reducing work pressure and improving health behavior among clinical and anesthesia frontline nurses. Methods: We used convenience sampling to select clinical and anesthesiology department nurses from hospitals between May 2019 and May 2021. We used a nursing knowledge-attitude-behavior questionnaire to assess the status of nurses and assess the effectiveness of the narrative therapy intervention. We analyzed our data using SPSS and Smart PLS. Results: We found statistically significant differences in scores on the Competence Scale (NCS) and the Nursing Caring Characters Assessment Tool (NCCAT) (p<.05). The average scores of items in each dimension of clinical and anesthesiology department narrative nursing knowledge and behavior were: knowledge score (3.67±0.52), attitude score (5.48±0.62), and behavior score (4.74±0.77). Conclusion: The ADDIE-based narrative nursing training program improved nurses' narrative nursing ability and humanistic care quality, reducing work pressure and promoting health behavior. These findings highlight the importance of narrative therapy in clinical practice for frontline nurses.
Anesthesia , Narrative Therapy , Nurses , Humans , Health Behavior , Quality of Health Care
Paeonia ostii is a worldwide ornamental flower and an emerging oil crop. Zyotic embryogenesis is a critical process during seed development, and it can provide a basis for improving the efficiency of somatic embryogenesis (SE). In this study, transcriptome sequencing of embryo development was performed to investigate gene expression profiling in P. ostii and identified Differentially expressed genes (DEGs) related to transcription factors, plant hormones, and antioxidant enzymes. The results indicated that IAA (Indole-3-acetic acid), GA (Gibberellin), BR (Brassinosteroid) and ETH (Ethylene) were beneficial to early embryonic morphogenesis, while CTK (Cytokinin) and ABA (Abscisic Acid) promoted embryo morphogenesis and maturation. The antioxidant enzymes' activity was the highest in early embryos and an important participant in embryo formation. The high expression of the genes encoding fatty acid desaturase was beneficial to fast oil accumulation. Representative DEGs were selected and validated using qRT-PCR. Protein-protein interaction network (PPI) was predicted, and six central node proteins, including AUX1, PIN1, ARF6, LAX3, ABCB19, PIF3, and PIF4, were screened. Our results provided new insights into the formation of embryo development and even somatic embryo development in tree peonies.
Paeonia , Transcriptome , Humans , Paeonia/genetics , Paeonia/metabolism , Antioxidants/metabolism , Gene Expression Profiling , Embryonic Development/genetics , Gene Expression Regulation, Plant , NIMA-Interacting Peptidylprolyl Isomerase/metabolism
Breast cancer is the most common malignant tumor in women, which seriously threatens the life and health of patients. Therefore, facile and sensitive detection of human breast cancer cells is crucial for cancer diagnosis. In this work, plum-branched CdS/Bi2S3 heterostructures (CdS/Bi2S3 HSs) were synthesized under hydrothermal condition, whose photoelectrochemical (PEC) property and biocompatibility were scrutinously investigated. In parallel, a signal amplification strategy was designed based on immune recognition between epidermal growth factor receptor (EGFR) overexpressed on membrane of breast cancer cells MDA-MB-231 and its aptamer. Integration of the above together, a highly sensitive PEC cytosensor was developed for analysis of target MDA-MB-231 cells, exhibiting a wider linear range of 1 × 102 â¼ 3 × 105 cells mL-1 with a limit of detection (LOD) down to 6 cells mL-1 (S/N = 3). Further, the biosensor was explored for anticancer drug (e.g., dacomitinib) screening by monitoring the variations in the PEC signals of the expressed EGFR upon drug stimulation. The obtained CdS/Bi2S3 HSs are identified as promising and feasible photoactive material for determination of cancer cells and drug screening in clinic and related research.
Biosensing Techniques , Breast Neoplasms , Prunus domestica , Humans , Female , Electrochemical Techniques , Early Detection of Cancer , Breast Neoplasms/diagnosis , Limit of Detection , ErbB Receptors
Fumonisin B1 (FB1), the most prevalent and highest toxicity mycotoxins among fumonisins family, poses threats to human especially children and infants even at a trace level. Therefore, its facile and sensitive detection is of importance. Herein, Z-scheme Cu2MoS4/CdS/In2S3 nanocage-like heterojunctions (labeled Cu2MoS4/CdS/In2S3) were synthesized, whose photoelectrochemical (PEC) property and electron transfer mechanism were strictly investigated. The Cu2MoS4/CdS/In2S3 behaved as photoactive substrate for building a PEC sensing platform for detection of FB1, integrated with PtPd alloy modified hollow CoSnO3 nanoboxes (labeled PtPd-CoSnO3) nanozyme. By virtue of the stronger affinity between the target FB1 and its aptamer (FB1-Apt), the photocurrent was recovered by releasing the CoSnO3-PtPd3 modified FB1-Apt (FB1-Apt/PtPd-CoSnO3) from the photoanode, which can terminate the catalytic precipitation reaction for its peroxidase-like property. The resultant PEC aptasensor exhibited a wider dynamic linear range from 1 × 10-4 to 1 × 102 ng mL-1 with a lower limit of detection (0.0723 pg mL-1). Thus, this research provides a feasible PEC sensing platform for routine analysis of other mycotoxins in practice.
Aptamers, Nucleotide , Biosensing Techniques , Fumonisins , Child , Humans , Electrochemical Techniques , Fumonisins/chemistry , Aptamers, Nucleotide/chemistry , Limit of Detection
The emergence of recombinant viruses is a threat to public health, as recombination may integrate variant-specific features that together result in escape from treatment or immunity. The selective advantages of recombinant SARS-CoV-2 isolates over their parental lineages remain unknown. We identified a Delta-Omicron (AY.45-BA.1) recombinant in an immunosuppressed transplant recipient treated with monoclonal antibody Sotrovimab. The single recombination breakpoint is located in the spike N-terminal domain adjacent to the Sotrovimab binding site. While Delta and BA.1 are sensitive to Sotrovimab neutralization, the Delta-Omicron recombinant is highly resistant. To our knowledge, this is the first described instance of recombination between circulating SARS-CoV-2 variants as a functional mechanism of resistance to treatment and immune escape.
As one of the most toxic chemical substances, aflatoxin B1 (AFB1) has a strong carcinogenic effect even at a trace level in human and animal, which severely threatens human health and even causes cancers. Therefore, ultrasensitive detection of AFB1 is of significant importance. For such analysis, dual II-scheme sheet-like Bi2S3/Bi2O3/Ag2S heterostructures were prepared by the in-situ growth method, which exhibited high separation efficiency for the electron-hole (e--h+) pairs, prominent stability, and high photoactivity. Moreover, the dendritic nanorod-like Au@Pd@Pt (Au@Pd@Pt DNRs) nanozyme was homely synthesized, whose peroxidase-like activity was scrupulously investigated by catalytical oxidation of diaminobenzidine (DAB) in the presence of H2O2. Integration by the aptasensing strategy, a photoelectrochemical (PEC) "signal-on" aptasensor was prepared, which exhibited a broader linear range of 0.5 pg mL-1-100 ng mL-1 with a lower limit of detection (LOD = 0.09 pg mL-1, S/N = 3). This work provides a feasible strategy to develop advanced PEC biosensors for actual analysis of environmental pollutants.
Aptamers, Nucleotide , Biosensing Techniques , Nanotubes , Animals , Humans , Biosensing Techniques/methods , Aflatoxin B1/analysis , Hydrogen Peroxide , Aptamers, Nucleotide/chemistry , Electrochemical Techniques/methods , Limit of Detection , Nanotubes/chemistry
New mutations conferring resistance to SARS-CoV-2 therapeutics have important clinical implications. We describe the first cases of an independently acquired V792I RNA-dependent RNA polymerase mutation developing in renal transplant recipients after remdesivir exposure. Our work underscores the need for augmented efforts to identify concerning mutations and address their clinical implications.
COVID-19 , Humans , SARS-CoV-2 , Antiviral Agents/therapeutic use , Transplant Recipients , COVID-19 Drug Treatment
Low-density lipoprotein receptor (LDLR) mediates clearance of plasma LDL cholesterol, preventing the development of atherosclerosis. We previously demonstrated that membrane type 1-matrix metalloproteinase (MT1-MMP) cleaves LDLR and exacerbates the development of atherosclerosis. Here, we investigated determinants in LDLR and MT1-MMP that were critical for MT1-MMP-induced LDLR cleavage. We observed that deletion of various functional domains in LDLR or removal of each of the five predicted cleavage sites of MT1-MMP on LDLR did not affect MT1-MMP-induced cleavage of the receptor. Removal of the hemopexin domain or the C-terminal cytoplasmic tail of MT1-MMP also did not impair its ability to cleave LDLR. On the other hand, mutant MT1-MMP, in which the catalytic domain or the MT-loop was deleted, could not cleave LDLR. Further Ala-scanning analysis revealed an important role for Ile at position 167 of the MT-loop in MT1-MMP's action on LDLR. Replacement of Ile167 with Ala, Thr, Glu, or Lys resulted in a marked loss of the ability to cleave LDLR, whereas mutation of Ile167 to a non-polar amino acid residue, including Leu, Val, Met, and Phe, had no effect. Therefore, our studies indicate that MT1-MMP does not require a specific cleavage site on LDLR. In contrast, an amino acid residue with a hydrophobic side chain at position 167 in the MT-loop is critical for MT1-MMP-induced LDLR cleavage.
Background: Adiponectin is a recognized antiatherogenic molecule; this study was aimed at clarifying the effects of adiponectin variants on lipid and adiponectin levels. Methods: By searching PubMed and Cochrane databases for studies published before March 31, 2022, a total of 86,610 individuals were included in the analysis. Results: Variants of rs2241766 and rs266729 were associated with decreased adiponectin and high-density lipoprotein cholesterol (HDL-C), as well as increased triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels. In contrast, the rs1501299 variant was correlated with increased adiponectin and HDL-C, as well as decreased TG, TC, and LDL-C levels. Subgroup analysis indicated that the significant effect of the rs2241766 and rs266729 variants on lipid profile was predominant in Chinese, while the significant effect of the rs1501299 variant on lipid profile was primarily in Caucasians. Moreover, a stronger effect of the rs2241766 and rs1501299 variants on LDL-C levels was observed in males, while a considerable effect of the rs266729 variant on LDL-C levels was observed in children. Conclusions: The present study indicated that Chinese with the rs2241766 and rs266729 variants were at high risk of dyslipidemia, atherosclerosis, or coronary artery disease (CAD). Males with the rs2241766 variant were at high risk of CAD. Children with the rs266729 variant had a high risk to develop dyslipidemia, atherosclerosis, and even early onset of CAD in the future. These findings are beneficial to clinical physicians to choose different management strategies for cardiovascular disease (CVD) prevention.
Atherosclerosis , Coronary Artery Disease , Dyslipidemias , Adiponectin/blood , Adiponectin/genetics , Atherosclerosis/blood , Atherosclerosis/genetics , Child , Cholesterol, LDL , Coronary Artery Disease/blood , Coronary Artery Disease/genetics , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/epidemiology , Dyslipidemias/genetics , Female , Humans , Male , Multicenter Studies as Topic , Polymorphism, Single Nucleotide
Hepatocellular carcinoma is a life-threatening malignant tumor found around the world for its high morbidity and mortality. Therefore, it is of great importance for sensitive analysis of liver cancer cells (HepG2 cells) in clinical diagnosis and biomedical research. To fulfill this demand, hollow CdIn2S4/In2S3 heterostructured microspheres (termed CdIn2S4/In2S3 for clarity) were prepared by a two-step hydrothermal strategy and applied for building a novel photoelectrochemical (PEC) cytosensor for ultrasensitive and accurate detection of HepG2 cells through specific recognition of CD133 protein on the cell surface with the respective aptamer. The optical properties of CdIn2S4/In2S3 were investigated by UV-vis diffuse reflectance spectroscopy (DRS) and PEC technology. By virtue of their appealing PEC characteristics, the resultant PEC sensor exhibited a wider dynamic linear range from 1 × 102 to 2 × 105 cells mL-1 with a lower limit of detection (LOD, 23 cells mL-1), combined by evaluating the expression level of CD133 protein stimulated by metformin as a benchmarked inhibitor. This work opens a valuable and feasible avenue for sensitive detection of diverse tumor cells, holding great potential in early clinical diagnosis and treatment coupled by screening inhibitors.
Biosensing Techniques , Electrochemical Techniques , Electrochemical Techniques/methods , Hep G2 Cells , Humans , Microspheres
BACKGROUND: In 2021, Delta became the predominant SARS-CoV-2 variant worldwide. While vaccines have effectively prevented COVID-19 hospitalization and death, vaccine breakthrough infections increasingly occurred. The precise role of clinical and genomic determinants in Delta infections is not known, and whether they contributed to increased rates of breakthrough infections compared to unvaccinated controls. METHODS: We studied SARS-CoV-2 variant distribution, dynamics, and adaptive selection over time in relation to vaccine status, phylogenetic relatedness of viruses, full genome mutation profiles, and associated clinical and demographic parameters. FINDINGS: We show a steep and near-complete replacement of circulating variants with Delta between May and August 2021 in metropolitan New York. We observed an increase of the Delta sublineage AY.25 (14% in vaccinated, 7% in unvaccinated), its spike mutation S112L, and AY.44 (8% in vaccinated, 2% in unvaccinated) with its nsp12 mutation F192V in breakthroughs. Delta infections were associated with younger age and lower hospitalization rates than Alpha. Delta breakthrough infections increased significantly with time since vaccination, and, after adjusting for confounders, they rose at similar rates as in unvaccinated individuals. INTERPRETATION: We observed a modest adaptation of Delta genomes in breakthrough infections in New York, suggesting an improved genomic framework to support Delta's epidemic growth in times of waning vaccine protection despite limited impact on vaccine escape. FUNDING: The study was supported by NYU institutional funds. The NYULH Genome Technology Center is partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center.
COVID-19 , SARS-CoV-2 , COVID-19/epidemiology , COVID-19/genetics , Genomics , Humans , New York/epidemiology , Phylogeny , SARS-CoV-2/genetics
