Alzheimer's disease risk allele of PICALM causes detrimental lipid droplets in microglia.

Despite genome-wide association studies of late-onset Alzheimer's disease (LOAD) having identified many genetic risk loci 1-6, the underlying disease mechanisms remain largely unknown. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Leveraging our approach for identifying functional GWAS risk variants showing allele-specific open chromatin (ASoC) 7, we systematically identified putative causal LOAD risk variants in human induced pluripotent stem cells (iPSC)-derived neurons, astrocytes, and microglia (MG) and linked PICALM risk allele to a previously unappreciated MG-specific role of PICALM in lipid droplet (LD) accumulation. ASoC mapping uncovered functional risk variants for 26 LOAD risk loci, mostly MG-specific. At the MG-specific PICALM locus, the LOAD risk allele of rs10792832 reduced transcription factor (PU.1) binding and PICALM expression, impairing the uptake of amyloid beta (Aß) and myelin debris. Interestingly, MG with PICALM risk allele showed transcriptional enrichment of pathways for cholesterol synthesis and LD formation. Genetic and pharmacological perturbations of MG further established a causal link between the reduced PICALM expression, LD accumulation, and phagocytosis deficits. Our work elucidates the selective LOAD vulnerability in microglia for the PICALM locus through detrimental LD accumulation, providing a neurobiological basis that can be exploited for developing novel clinical interventions.

Observation of Bose-Einstein condensation of dipolar molecules.

Ensembles of particles governed by quantum mechanical laws exhibit intriguing emergent behaviour. Atomic quantum gases1,2, liquid helium3,4 and electrons in quantum materials5-7 all exhibit distinct properties because of their composition and interactions. Quantum degenerate samples of ultracold dipolar molecules promise the realization of new phases of matter and new avenues for quantum simulation8 and quantum computation9. However, rapid losses10, even when reduced through collisional shielding techniques11-13, have so far prevented evaporative cooling to a Bose-Einstein condensate (BEC). Here we report on the realization of a BEC of dipolar molecules. By strongly suppressing two- and three-body losses via enhanced collisional shielding, we evaporatively cool sodium-caesium molecules to quantum degeneracy and cross the phase transition to a BEC. The BEC reveals itself by a bimodal distribution when the phase-space density exceeds 1. BECs with a condensate fraction of 60(10)% and a temperature of 6(2) nK are created and found to be stable with a lifetime close to 2 s. This work opens the door to the exploration of dipolar quantum matter in regimes that have been inaccessible so far, promising the creation of exotic dipolar droplets14, self-organized crystal phases15 and dipolar spin liquids in optical lattices16.

Overcome the Limitation of Phenome-Wide Association Studies (PheWAS): Extension of PheWAS to Efficient and Robust Large-Scale ICD Codes Analysis.

The Phenome-wide association studies (PheWAS) have become widely used for efficient, high-throughput evaluation of relationship between a genetic factor and a large number of disease phenotypes, typically extracted from a DNA biobank linked with electronic medical records (EMR). Phecodes, billing code-derived disease case-control status, are usually used as outcome variables in PheWAS and logistic regression has been the standard choice of analysis method. Since the clinical diagnoses in EMR are often inaccurate with errors which can lead to biases in the odds ratio estimates, much effort has been put to accurately define the cases and controls to ensure an accurate analysis. Specifically in order to correctly classify controls in the population, an exclusion criteria list for each Phecode was manually compiled to obtain unbiased odds ratios. However, the accuracy of the list cannot be guaranteed without extensive data curation process. The costly curation process limits the efficiency of large-scale analyses that take full advantage of all structured phenotypic information available in EMR. Here, we proposed to estimate relative risks (RR) instead. We first demonstrated the desired nature of RR that overcomes the inaccuracy in the controls via theoretical formula. With simulation and real data application, we further confirmed that RR is unbiased without compiling exclusion criteria lists. With RR as estimates, we are able to efficiently extend PheWAS to a larger-scale, phenome construction agnostic analysis of phenotypes, using ICD 9/10 codes, which preserve much more disease-related clinical information than Phecodes.

The Brassinosteroid Receptor StBRI1 Promotes Tuber Development by Enhancing Plasma Membrane H+-ATPase Activity in Potato.

The brassinosteroid (BR) receptor BRASSINOSTEROID-INSENSITIVE 1 (BRI1) plays a critical role in plant growth and development. Although much is known about how BR signaling regulates growth and development in many crop species, the role of StBRI1 in regulating potato (Solanum tuberosum) tuber development is not well understood. To address this question, a series of comprehensive genetic and biochemical methods were applied in this investigation. It was determined that StBRI1 and Solanum tuberosum PLASMA MEMBRANE (PM) PROTON ATPASE2 (PHA2), a PM-localized proton ATPase, play important roles in potato tuber development. The individual overexpression of StBRI1 and PHA2 led to a 22% and 25% increase in tuber yield per plant, respectively. Consistent with the genetic evidence, in vivo interaction analysis using double transgenic lines and PM H+-ATPase activity assays indicated that StBRI1 interacts with the C-terminus of PHA2, which restrains the intramolecular interaction of the PHA2 C-terminus with the PHA2 central loop to attenuate autoinhibition of PM H+-ATPase activity, resulting in increased PHA2 activity. Furthermore, the extent of PM H+-ATPase autoinhibition involving phosphorylation-dependent mechanisms corresponds to phosphorylation of the penultimate Thr residue (Thr-951) in PHA2. These results suggest that StBRI1 phosphorylates PHA2 and enhances its activity, which subsequently promotes tuber development. Altogether, our results uncover a BR-StBRI1-PHA2 module that regulates tuber development and suggest a prospective strategy for improving tuberous crop growth and increasing yield via the cell surface-based BR signaling pathway.

Interoperability of phenome-wide multimorbidity patterns: a comparative study of two large-scale EHR systems.

Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administrative purposes raise questions about the consistency and reproducibility of EHR-based multimorbidity research. Methods: Utilizing phecodes to represent the disease phenome, we analyzed pairwise comorbidity strengths using a dual logistic regression approach and constructed multimorbidity as an undirected weighted graph. We assessed the consistency of the multimorbidity networks within and between two major EHR systems at local (nodes and edges), meso (neighboring patterns), and global (network statistics) scales. We present case studies to identify disease clusters and uncover clinically interpretable disease relationships. We provide an interactive web tool and a knowledge base combining data from multiple sources for online multimorbidity analysis. Findings: Analyzing data from 500,000 patients across Vanderbilt University Medical Center and Mass General Brigham health systems, we observed a strong correlation in disease frequencies (Kendall's τ = 0.643) and comorbidity strengths (Pearson ρ = 0.79). Consistent network statistics across EHRs suggest similar structures of multimorbidity networks at various scales. Comorbidity strengths and similarities of multimorbidity connection patterns align with the disease genetic correlations. Graph-theoretic analyses revealed a consistent core-periphery structure, implying efficient network clustering through threshold graph construction. Using hydronephrosis as a case study, we demonstrated the network's ability to uncover clinically relevant disease relationships and provide novel insights. Interpretation: Our findings demonstrate the robustness of large-scale EHR data for studying phenome-wide multimorbidities. The alignment of multimorbidity patterns with genetic data suggests the potential utility for uncovering shared biology of diseases. The consistent core-periphery structure offers analytical insights to discover complex disease interactions. This work also sets the stage for advanced disease modeling, with implications for precision medicine. Funding: VUMC Biostatistics Development Award, the National Institutes of Health, and the VA CSRD.

Enhancing therapeutic efficacy in luminal androgen receptor triple-negative breast cancer: exploring chidamide and enzalutamide as a promising combination strategy.

Extensive exploration of the molecular subtypes of triple-negative breast cancer (TNBC) is critical for advancing precision medicine. Notably, the luminal androgen receptor (LAR) subtype has attracted attention for targeted treatment combining androgen receptor antagonists and CDK4/6 inhibitors. Unfortunately, this strategy has proven to be of limited efficacy, highlighting the need for further optimization. Using our center's comprehensive multiomics dataset (n = 465), we identified novel therapeutic targets and evaluated their efficacy through multiple models, including in vitro LAR cell lines, in vivo cell-derived allograft models and ex vivo patient-derived organoids. Moreover, we conducted flow cytometry and RNA-seq analysis to unveil potential mechanisms underlying the regulation of tumor progression by these therapeutic strategies. LAR breast cancer cells exhibited sensitivity to chidamide and enzalutamide individually, with a drug combination assay revealing their synergistic effect. Crucially, this synergistic effect was verified through in vivo allograft models and patient-derived organoids. Furthermore, transcriptomic analysis demonstrated that the combination therapeutic strategy could inhibit tumor progression by regulating metabolism and autophagy. This study confirmed that the combination of histone deacetylase (HDAC) inhibitors and androgen receptor (AR) antagonists possessed greater therapeutic efficacy than monotherapy in LAR TNBC. This finding significantly bolsters the theoretical basis for the clinical translation of this combination therapy and provides an innovative strategy for the targeted treatment of LAR TNBC.

Scaled and Efficient Derivation of Loss of Function Alleles in Risk Genes for Neurodevelopmental and Psychiatric Disorders in Human iPSC.

Translating genetic findings for neurodevelopmental and psychiatric disorders (NPD) into actionable disease biology would benefit from large-scale and unbiased functional studies of NPD genes. Leveraging the cytosine base editing (CBE) system, here we developed a pipeline for clonal loss-of-function (LoF) allele mutagenesis in human induced pluripotent stem cells (hiPSCs) by introducing premature stop-codons (iSTOP) that lead to mRNA nonsense-mediated-decay (NMD) or protein truncation. We tested the pipeline for 23 NPD genes on 3 hiPSC lines and achieved highly reproducible, efficient iSTOP editing in 22 NPD genes. Using RNAseq, we confirmed their pluripotency, absence of chromosomal abnormalities, and NMD. Interestingly, for three schizophrenia risk genes (SETD1A, TRIO, CUL1), despite the high efficiency of base editing, we only obtained heterozygous LoF alleles, suggesting their essential roles for cell growth. We replicated the reported neural phenotypes of SHANK3-haploinsufficiency and found CUL1-LoF reduced neurite branches and synaptic puncta density. This iSTOP pipeline enables a scaled and efficient LoF mutagenesis of NPD genes, yielding an invaluable shareable resource.

Integrating Electronic Health Records and Polygenic Risk to Identify Genetically Unrelated Comorbidities of Schizophrenia That May Be Modifiable.

Background: Patients with schizophrenia have substantial comorbidity that contributes to reduced life expectancy of 10 to 20 years. Identifying modifiable comorbidities could improve rates of premature mortality. Conditions that frequently co-occur but lack shared genetic risk with schizophrenia are more likely to be products of treatment, behavior, or environmental factors and therefore are enriched for potentially modifiable associations. Methods: Phenome-wide comorbidity was calculated from electronic health records of 250,000 patients across 2 independent health care institutions (Vanderbilt University Medical Center and Mass General Brigham); associations with schizophrenia polygenic risk scores were calculated across the same phenotypes in linked biobanks. Results: Schizophrenia comorbidity was significantly correlated across institutions (r = 0.85), and the 77 identified comorbidities were consistent with prior literature. Overall, comorbidity and polygenic risk score associations were significantly correlated (r = 0.55, p = 1.29 × 10-118). However, directly testing for the absence of genetic effects identified 36 comorbidities that had significantly equivalent schizophrenia polygenic risk score distributions between cases and controls. This set included phenotypes known to be consequences of antipsychotic medications (e.g., movement disorders) or of the disease such as reduced hygiene (e.g., diseases of the nail), thereby validating the approach. It also highlighted phenotypes with less clear causal relationships and minimal genetic effects such as tobacco use disorder and diabetes. Conclusions: This work demonstrates the consistency and robustness of electronic health record-based schizophrenia comorbidities across independent institutions and with the existing literature. It identifies known and novel comorbidities with an absence of shared genetic risk, indicating other causes that may be modifiable and where further study of causal pathways could improve outcomes for patients.

Patients with schizophrenia have many co-occurring diseases that contribute substantially to premature mortality of 10 to 20 years. Conditions that are comorbid but lack shared genetic risk with schizophrenia are likely to have causes that are more modifiable. Here, we calculated comorbidity from electronic health records from 2 independent health care institutions and associations with schizophrenia polygenic risk scores across the same phenotypes in linked biobanks. We identified known and novel diseases comorbid with schizophrenia, thereby validating our approach.

Investigation of the formation mechanism of the pepper starch-piperine complex.

In this study, a new carrier for loading piperine was prepared using pepper starch, and its interaction mechanism was investigated. The porous pepper starch-piperine complex (PPS-PIP) showed higher loading efficiency (76.15 %) compared to the porous corn starch-piperine complex (PCS-PIP (52.34 %)). This may be ascribed to the hemispherical shell structure of porous pepper starch (PPS) compared to the porous structure of porous corn starch (PCS) based on the SEM result. PPS-PIP had smaller particle size (10.53 µm), higher relative crystallinity (38.95 %), and better thermal stability (87.45 °C) than PCS-PIP (17.37 µm, 32.17 %, 74.35 °C). Fourier transform infrared spectroscopy (FTIR) results implied that piperine not only forms a complex with amylose but may also be physically present in porous starch. This was demonstrated by the short-range order and X-ray type. Molecular dynamics simulations confirmed that hydrogen bonding is the primary interaction between amylose and piperine. Besides the formation of the amylose-piperine complex, some of the piperine is also present in physical form.

Turning Non-Emissive Schiff Bases Into Aggregate Emitters.

Schiff bases are a crucial component in various functional materials but often exhibit non-emissive behavior which significantly limits their potential applications as luminescent materials. However, traditional approaches to convert them into aggregate emitters often require intricate molecular design, tedious synthesis, and significant time and resource consumption. Herein, we present a cocrystallization-induced emission strategy that can transform non-emissive (hetero)aryl-substituted Schiff bases into green-yellow to yellow aggregate emitters via even simple grinding of a mixture of Schiff bases and 1,2,4,5-tetracyanobenzene (TCB) mixtures. The combined experimental and theoretical analysis revealed that the cocrystallization inhibits the C=N isomerization and promotes face-to-face π-π interaction, which restricts access to both the dark state and canonical intersection to ultimately induce emission. Furthermore, the induced emission enables the observation of solid-state molecular diffusion through fluorescence signals, advancing white light emission diodes, and notably, solution-processed organic light-emitting diodes based on cocrystal for the first time. This study not only highlights the potential of developing new C=N structural motifs for AIEgens but also could boost advancements in related structure motifs like C=C and N=N.

The number of test organisms might influence the toxicity evaluation of hydrophobic micropollutants.

Evaluating the toxicity of micropollutants forms the basis for understanding their potential risks to the ecosystem and/or human health. To accurately evaluate the toxicity of micropollutants in toxicity tests, many factors have been carefully considered, while the impact of the number of test organisms on toxicity results has rarely been taken into account. In this study, the role of the organism number on the developmental toxicity of five micropollutants was investigated using embryos of the marine polychaete Platynereis dumerilii. The toxicity of hydrophobic micropollutants was found to decrease significantly with increasing the number of embryos used in the test. A quantitative model was developed to better describe how the number of embryos affected developmental toxicity. The model showed a satisfactory fit to the raw data in all scenarios tested. The intrinsic half-maximal effective concentration EC50,int was then determined using the model. For a given compound, the EC50,int was a stable parameter that did not depend on the number of test embryos and thus provided an indication of the intrinsic toxicity of the compounds tested. Compared with the EC50 values determined with the commonly used embryo number (around 120), the EC50,int values of all tested hydrophobic micropollutants were lower. The more hydrophobic the compounds tested, the more pronounced the reduction in toxicity. This suggested that hydrophobic micropollutants could be more toxic than reported in the literature. Some suggestions were also made to eliminate the effect of the number of organisms used in the toxicity evaluation.

Molecular regulation of the key specialized metabolism pathways in medicinal plants.

The basis of modern pharmacology is the human ability to exploit the production of specialized metabolites from medical plants, for example, terpenoids, alkaloids, and phenolic acids. However, in most cases, the availability of these valuable compounds is limited by cellular or organelle barriers or spatio-temporal accumulation patterns within different plant tissues. Transcription factors (TFs) regulate biosynthesis of these specialized metabolites by tightly controlling the expression of biosynthetic genes. Cutting-edge technologies and/or combining multiple strategies and approaches have been applied to elucidate the role of TFs. In this review, we focus on recent progress in the transcription regulation mechanism of representative high-value products and describe the transcriptional regulatory network, and future perspectives are discussed, which will help develop high-yield plant resources.

Boosting Luminescence Efficiency of Near-Infrared-II Aggregation-Induced Emission Luminogens via a Mash-Up Strategy of π-Extension and Deuteration for Dual-Model Image-Guided Surgery.

The simultaneous pursuit of accelerative radiative and restricted nonradiative decay is of tremendous significance to construct high-luminescence-efficiency fluorophores in the second near-infrared wavelength window (NIR-II), which is seriously hindered by the energy gap laws. Herein, a mash-up strategy of π-extension and deuteration is proposed to efficaciously ameliorate the knotty problem. By extending the π-conjugation of the aromatic fragment and introducing an isotope effect to the aggregation-induced emission luminogen (AIEgen), an improved oscillator strength (f), coupled with suppressed deformation and high-frequency oscillation in the excited state, are successively implemented. In this case, a faster rate of radiative decay (kr) and restricted nonradiative decay (knr) are simultaneously achieved. Moreover, the preeminent emissive property of AIEgen in the molecular state could be commendably inherited by the aggregates. The corresponding NIR-II emissive AIEgen-based nanoparticles display high brightness, large Stokes shift, and superior photostability simultaneously, which can be applied for image-guided cancer and sentinel lymph node (SLN) surgery. This work thus provides a rational roadmap to improve the luminescence efficiency of NIR-II fluorophores for biomedical applications.

Mining of disease-resistance genes in Crocus sativus based on transcriptome sequencing.

Introduction: Crocus sativus L. has an important medicinal and economic value in traditional perennial Chinese medicine. However, due to its unique growth characteristics, during cultivation it is highly susceptible to disease. The absence of effective resistance genes restricts us to breed new resistant varieties of C. sativus. Methods: In present study, comprehensive transcriptome sequencing was introduced to explore the disease resistance of the candidate gene in healthy and corm rot-infected C. sativus. Results and discussion: Totally, 43.72 Gb of clean data was obtained from the assembly to generate 65,337 unigenes. By comparing the gene expression levels, 7,575 differentially expressed genes (DEGs) were primarily screened. A majority of the DEGs were completely in charge of defense and metabolism, and 152 of them were annotated as pathogen recognition genes (PRGs) based on the PGRdb dataset. The expression of some transcription factors including NAC, MYB, and WRKY members, changed significantly based on the dataset of transcriptome sequencing. Therefore, this study provides us some valuable information for exploring candidate genes involved in the disease resistance in C. sativus.

Evaluation of genetic associations with clinical phenotypes of kidney stone disease.

Introduction and Objective: We sought to replicate and discover genetic associations of kidney stone disease within a large-scale electronic health record (EHR) system. Methods: We performed genome-wide association studies (GWASs) for nephrolithiasis from genotyped samples of 5,571 cases and 83,692 controls. Among the significant risk variants, we performed association analyses of stone composition and first-time 24-hour urine parameters. To assess disease severity, we investigated the associations of risk variants with age at first stone diagnosis, age at first procedure, and time from first to second procedure. Results: The main GWAS analysis identified 10 significant loci, each located on chromosome 16 within coding regions of the UMOD gene, which codes for uromodulin, a urine protein with inhibitory activity for calcium crystallization. The strongest signal was from SNP 16:20359633-C-T (odds ratio [OR] 1.17, 95% CI 1.11-1.23), with the remaining significant SNPs having similar effect sizes. In subgroup GWASs by stone composition, 19 significant loci were identified, of which two loci were located in coding regions (brushite; NXPH1 , rs79970906 and rs4725104). The UMOD SNP 16:20359633-C-T was associated with differences in 24-hour excretion of urinary calcium, uric acid, phosphorus, sulfate; and the minor allele was positively associated with calcium oxalate dihydrate stone composition (p<0.05). No associations were found between UMOD variants and disease severity. Conclusions: We replicated germline variants associated with kidney stone disease risk at UMOD and reported novel variants associated with stone composition. Genetic variants of UMOD are associated with differences in 24-hour urine parameters and stone composition, but not disease severity.

Bright, photostable and long-circulating NIR-II nanoparticles for whole-process monitoring and evaluation of renal transplantation.

Kidney transplantation is the gold standard for the treatment of end-stage renal diseases (ESRDs). However, the scarcity of donor kidneys has caused more and more ESRD patients to be stuck on the waiting list for transplant surgery. Improving the survival rate for renal grafts is an alternative solution to the shortage of donor kidneys. Therefore, real-time monitoring of the surgical process is crucial to the success of kidney transplantation, but efficient methods and techniques are lacking. Herein, a fluorescence technology based on bright, photostable and long-circulating aggregation-induced emission (AIE) active NIR-II nano-contrast agent DIPT-ICF nanoparticles for the whole-process monitoring and evaluation of renal transplantation has been reported. In the aggregated state, DIPT-ICF exhibits superior photophysical properties compared with the commercial dyes IR-26 and IR-1061. Besides, the long-circulating characteristic of the AIE nano-contrast agent helps to achieve renal angiography in kidney retrieval surgery, donor kidney quality evaluation, diagnosing vascular and ureteral complications, and assessment of renal graft reperfusion beyond renovascular reconstruction, which considerably outperforms the clinically approved indocyanine green (ICG).

Transcriptome Analysis of Salvia miltiorrhiza under Drought Stress.

Phenolic acids are one of the major secondary metabolites accumulated in Salvia miltiorrhiza with various pharmacological activities. Moderate drought stress can promote the accumulation of phenolic acids in S. miltiorrhiza, while the mechanism remains unclear. Therefore, we performed transcriptome sequencing of S. miltiorrhiza under drought treatment. A total of 47,169 unigenes were successfully annotated in at least one of the six major databases. Key enzyme genes involved in the phenolic acid biosynthetic pathway, including SmPAL, SmC4H, Sm4CL, SmTAT, SmHPPR, SmRAS and SmCYP98A14, were induced. Unigenes annotated as laccase correlated with SmRAS and SmCYP98A14 were analyzed, and seven candidates that may be involved in the key step of SalB biosynthesis by RA were obtained. A total of 15 transcription factors significantly up-regulated at 2 h and 4 h potentially regulating phenolic acid biosynthesis were screened out. TRINITY_DN14213_c0_g1 (AP2/ERF) significantly transactivated the expression of SmC4H and SmRAS, suggesting its role in the regulation of phenolic acid biosynthesis. GO and KEGG enrichment analysis of differential expression genes showed that phenylpropanoid biosynthesis and plant hormone signal transduction were significantly higher. The ABA-dependent pathway is essential for resistance to drought and phenolic acid accumulation. Expression patterns in drought and ABA databases showed that four PYLs respond to both drought and ABA, and three potential SnRK2 family members were annotated and analyzed. The present study presented a comprehensive transcriptome analysis of S. miltiorrhiza affected by drought, which provides a rich source for understanding the molecular mechanism facing abiotic stress in S. miltiorrhiza.

Photopolymerized multifunctional sodium alginate-based hydrogel for antibacterial and coagulation dressings.

Trauma caused by tissue damage in clinical applications has posed a serious threat to public safety. Dressings with a single function cannot meet the needs of wound healing, but multifunctional dressings are difficult to achieve and obtain. To address this issue, this research designed a facile one-pot photo-crosslinking method to prepare multifunctional sodium alginate-based hydrogel dressings for effective wound healing. According to irregular wounds, sodium alginate-based hydrogel dressings can be quickly prepared anytime and anywhere. The structure and physicochemical properties of hydrogels are regulated by modulating the proportion of main components sodium alginate and acrylamide. The results showed the sodium alginate-based composite hydrogel as a candidate multifunctional dressing that exhibits excellent stretchability and compressibility, viscoelasticity, and suitable tissue-like adhesion. In vitro drug release and antibacterial experiments indicated that the hydrogel has effective antibacterial properties against S. aureus and P. aeruginosa. Furthermore, the haemostatic behaviour of the hydrogel was demonstrated using the coagulation activation test, whole blood-clotting test, and blood cell and platelet adhesion experiments. All these results demonstrated that the sodium alginate-based hydrogel had high application potential as a multifunctional medical dressing for wound healing.

Long-term health risk of offspring born from assisted reproductive technologies.

Since the world's first in vitro fertilization baby was born in 1978, there have been more than 8 million children conceived through assisted reproductive technologies (ART) worldwide, and a significant proportion of them have reached puberty or young adulthood. Many studies have found that ART increases the risk of adverse perinatal outcomes, including preterm birth, low birth weight, small size for gestational age, perinatal mortality, and congenital anomalies. However, data regarding the long-term outcomes of ART offspring are limited. According to the developmental origins of health and disease theory, adverse environments during early life stages may induce adaptive changes and subsequently result in an increased risk of diseases in later life. Increasing evidence also suggests that ART offspring are predisposed to an increased risk of non-communicable diseases, such as malignancies, asthma, obesity, metabolic syndrome, diabetes, cardiovascular diseases, and neurodevelopmental and psychiatric disorders. In this review, we summarize the risks for long-term health in ART offspring, discuss the underlying mechanisms, including underlying parental infertility, epigenetic alterations, non-physiological hormone levels, and placental dysfunction, and propose potential strategies to optimize the management of ART and health care of parents and children to eliminate the associated risks. Further ongoing follow-up and research are warranted to determine the effects of ART on the long-term health of ART offspring in later life.