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The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.
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Sequenciamento do Exoma , Genoma Humano , Genótipo , Hispânico ou Latino , Adulto , Humanos , África/etnologia , América/etnologia , Europa (Continente)/etnologia , Frequência do Gene/genética , Genética Populacional , Genoma Humano/genética , Técnicas de Genotipagem , Hispânico ou Latino/genética , Homozigoto , Mutação com Perda de Função/genética , México , Estudos ProspectivosRESUMO
Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes1-5. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes6, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.
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COVID-19 , Doenças Cardiovasculares , Humanos , Hematopoiese Clonal/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genéticaRESUMO
Predicting phenotypes from genotypes is a fundamental task in quantitative genetics. With technological advances, it is now possible to measure multiple phenotypes in large samples. Multiple phenotypes can share their genetic component; therefore, modeling these phenotypes jointly may improve prediction accuracy by leveraging effects that are shared across phenotypes. However, effects can be shared across phenotypes in a variety of ways, so computationally efficient statistical methods are needed that can accurately and flexibly capture patterns of effect sharing. Here, we describe new Bayesian multivariate, multiple regression methods that, by using flexible priors, are able to model and adapt to different patterns of effect sharing and specificity across phenotypes. Simulation results show that these new methods are fast and improve prediction accuracy compared with existing methods in a wide range of settings where effects are shared. Further, in settings where effects are not shared, our methods still perform competitively with state-of-the-art methods. In real data analyses of expression data in the Genotype Tissue Expression (GTEx) project, our methods improve prediction performance on average for all tissues, with the greatest gains in tissues where effects are strongly shared, and in the tissues with smaller sample sizes. While we use gene expression prediction to illustrate our methods, the methods are generally applicable to any multi-phenotype applications, including prediction of polygenic scores and breeding values. Thus, our methods have the potential to provide improvements across fields and organisms.
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Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Teorema de Bayes , Genótipo , Fenótipo , Simulação por Computador , Expressão GênicaRESUMO
In recent work, Wang et al introduced the "Sum of Single Effects" (SuSiE) model, and showed that it provides a simple and efficient approach to fine-mapping genetic variants from individual-level data. Here we present new methods for fitting the SuSiE model to summary data, for example to single-SNP z-scores from an association study and linkage disequilibrium (LD) values estimated from a suitable reference panel. To develop these new methods, we first describe a simple, generic strategy for extending any individual-level data method to deal with summary data. The key idea is to replace the usual regression likelihood with an analogous likelihood based on summary data. We show that existing fine-mapping methods such as FINEMAP and CAVIAR also (implicitly) use this strategy, but in different ways, and so this provides a common framework for understanding different methods for fine-mapping. We investigate other common practical issues in fine-mapping with summary data, including problems caused by inconsistencies between the z-scores and LD estimates, and we develop diagnostics to identify these inconsistencies. We also present a new refinement procedure that improves model fits in some data sets, and hence improves overall reliability of the SuSiE fine-mapping results. Detailed evaluations of fine-mapping methods in a range of simulated data sets show that SuSiE applied to summary data is competitive, in both speed and accuracy, with the best available fine-mapping methods for summary data.
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Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Funções Verossimilhança , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos TestesRESUMO
Conductive hydrogels have attracted widespread attention in the fields of biomedicine and health monitoring. However, their practical application is severely hindered by the lengthy and energy-intensive polymerization process and weak mechanical properties. Here, a rapid polymerization method of polyacrylic acid/gelatin double-network organohydrogel is designed by integrating tannic acid (TA) and Ag nanoparticles on conductive MXene nanosheets as catalyst in a binary solvent of water and glycerol, requiring no external energy input. The synergistic effect of TA and Ag NPs maintains the dynamic redox activity of phenol and quinone within the system, enhancing the efficiency of ammonium persulfate to generate radicals, leading to polymerization within 10 min. Also, ternary composite MXene@TA-Ag can act as conductive agents, enhanced fillers, adhesion promoters, and antibacterial agents of organohydrogels, granting them excellent multi-functionality. The organohydrogels exhibit excellent stretchability (1740%) and high tensile strength (184 kPa). The strain sensors based on the organohydrogels exhibit ultrahigh sensitivity (GF = 3.86), low detection limit (0.1%), and excellent stability (>1000 cycles, >7 days). These sensors can monitor the human limb movements, respiratory and vocal cord vibration, as well as various levels of arteries. Therefore, this organohydrogel holds potential for applications in fields such as human health monitoring and speech recognition.
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OBJECTIVE: Methyl CpG-binding protein 2 (MECP2) duplication syndrome is a rare X-linked genomic disorder affecting predominantly males, which is usually manifested as epilepsy and autism spectrum disorder (ASD) comorbidity. The transgenic line MeCP2Tg1 was used for mimicking MECP2 duplication syndrome and showed autism-epilepsy co-occurrence. Previous works suggested that the excitatory/inhibitory (E/I) imbalance is a potential common mechanism for both epilepsy and ASD. The projection neurons and parvalbumin (PV) interneurons account for the majority of E/I balance in the hippocampus. Therefore, we explored how structural changes of projection and PV+ neurons occur in the hippocampus of MeCP2Tg1 mice and whether these morphological changes contribute to epilepsy susceptibility. METHODS: We used the interneuron Designer receptors exclusively activated by designer drugs mouse model to inhibit inhibitory neurons in the hippocampus to verify the epilepsy susceptibility of MeCP2Tg1 (FVB, an inbred strain named as sensitivity to Friend leukemia virus) mice. Electroencephalograms were recorded for the definition of seizure. We performed retro-orbital injection of virus in MeCP2Tg1 (FVB):CaMKIIα-Cre (C57BL/6) mice or MeCP2Tg1:PV-Cre (C57BL/6) mice and their littermate controls to specifically label projection and PV+ neurons for structural analysis. RESULTS: Epilepsy susceptibility was increased in MeCP2Tg1 mice. There was a reduced number of PV neurons and reduced dendritic complexity in the hippocampus of MeCP2Tg1 mice. The dendritic complexity in MeCP2Tg1 mice was increased compared to wild-type mice, and total dendritic spine density in dentate gyrus of MeCP2Tg1 mice was also increased. Total dendritic spine density was increased in CA1 of MeCP2Tg1 mice. SIGNIFICANCE: Overexpression of MeCP2 may disrupt crucial signaling pathways, resulting in decreased dendritic complexity of PV interneurons and increased dendritic spine density of projection neurons. This reciprocal modulation of excitatory and inhibitory neuronal structures associated with MeCP2 implies its significance as a potential target in the development of epilepsy and offers a novel perspective on the co-occurrence of autism and epilepsy.
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Epilepsia , Hipocampo , Interneurônios , Parvalbuminas , Animais , Masculino , Camundongos , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/patologia , Epilepsia/genética , Hipocampo/patologia , Hipocampo/metabolismo , Interneurônios/patologia , Interneurônios/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos Transgênicos , Parvalbuminas/metabolismoRESUMO
Polychlorinated biphenyls (PCBs) affect multiple organs, and some of the effects are mediated by interfering with thyroid hormone (TH) signaling that regulates physiological processes in mammals. It remains unclear how PCBs affect skeletal muscle (SM). In our study, wistar rats were injected 2,3',4,4',5-pentachlorobiphenyl (PCB118) intraperitoneally at 0, 10, 100, and 1000 µg/kg/day for 13 weeks, and C2C12 myoblasts were treated PCB118 (0, 0.25, 25, and 50 nM) for 24 h or 48 h. We found that myocyte cross-sectional area (MCSA) was reduced, MyHC IIa and MyHC IIb mRNA levels significantly decreased, and muscle strength was weakened in PCB118-exposed rats. TH receptor α (TRα) and iodothyronine deiodinase type 2 (DIO2) were upregulated after PCB118 exposure both in vivo and in vitro. Transmission electron microscopy showed significant mitochondrial abnormalities in PCB118-treated rats, and the expression of mitochondrial regulators such as PTEN-induced kinase 1 (PINK1) and GTPase dynamin-related protein 1 (DRP1) were altered after PCB118 exposure. These results suggest that PCB118 could weaken muscle strength and attenuate fast-twitch fibers and fiber size of SM in rats. TH signaling, mitochondrial dynamics and mitophagy were also disturbed by PCB118, which may contribute to the alternations of SM structure and function.
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Bifenilos Policlorados , Animais , Mamíferos , Dinâmica Mitocondrial , Fibras Musculares Esqueléticas , Músculo Esquelético , Bifenilos Policlorados/toxicidade , Ratos , Ratos Wistar , Hormônios Tireóideos/metabolismoRESUMO
OBJECTIVE: The automatic generation of planning targets and auxiliary contours have achieved in Eclipse TPS 11.0. METHODS: The scripting language autohotkey was used to develop a software for automatically generated contours in Eclipse TPS. This software is named Contour Auto Margin (CAM), which is composed of operational functions of contours, script generated visualization and script file operations. RESULTS Ten cases in different cancers have separately selected, in Eclipse TPS 11.0 scripts generated by the software could not only automatically generate contours but also do contour post-processing. For different cancers, there was no difference between automatically generated contours and manually created contours. CONCLUSION: The CAM is a user-friendly and powerful software, and can automatically generated contours fast in Eclipse TPS 11.0. With the help of CAM, it greatly save plan preparation time and improve working efficiency of radiation therapy physicists.
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Planejamento da Radioterapia Assistida por Computador , Software , HumanosRESUMO
We introduce mvSuSiE, a multi-trait fine-mapping method for identifying putative causal variants from genetic association data (individual-level or summary data). mvSuSiE learns patterns of shared genetic effects from data, and exploits these patterns to improve power to identify causal SNPs. Comparisons on simulated data show that mvSuSiE is competitive in speed, power and precision with existing multi-trait methods, and uniformly improves on single-trait fine-mapping (SuSiE) in each trait separately. We applied mvSuSiE to jointly fine-map 16 blood cell traits using data from the UK Biobank. By jointly analyzing the traits and modeling heterogeneous effect sharing patterns, we discovered a much larger number of causal SNPs (>3,000) compared with single-trait fine-mapping, and with narrower credible sets. mvSuSiE also more comprehensively characterized the ways in which the genetic variants affect one or more blood cell traits; 68% of causal SNPs showed significant effects in more than one blood cell type.
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BACKGROUND: Chronic obstructive pulmonary disease (COPD) has emerged as a leading cause of chronic disease morbidity and mortality globally, posing a substantial public health challenge. Perfluoroalkyl substances (PFAS) are synthetic chemicals known for their high stability and durability. Research has examined their potential link to decreased lung function. Physical activity (PA) has been identified as one of the primary modalities of the non-pharmacological treatment of COPD. METHODS: To investigate the relationship between PFAS and COPD, and whether physical activity could reduce the risk of COPD caused by PFAS exposure, we used data from the NHANES 2013-2018, a cross-sectional study. Logistic regression analysis was used to examine the associations between PFAS and COPD in adult populations, and their associations in different PA types. RESULTS: We finally included 4857 participants in the analysis, and found that Sm-PFOS (OR: 1.250), PFOA (OR: 1.398) and n-PFOA (OR: 1.354) were closely related to COPD; After stratified by gender, age and smoking, the results showed that Sm-PFOA (OR: 1.312) was related to COPD in female adult, and PFOA (OR: 1.398) and n-PFOA (OR: 1.354) were associated with COPD in male adults; The associations of Sm-PFOS (OR: 1.280), PFOA (OR: 1.481) and n-PFOA (OR: 1.424)with COPD tended to be stronger and more consistent in over 50 years old adults; Sm-PFOS was related to COPD in current smoker (OR: 1.408), and PFOA was related to COPD in former smoker (OR: 1.487); Besides, in moderate-intensity PA group, there were no associations of Sm-PFOS, PFOA and n-PFOA with COPD stratified by gender, age and smoking. CONCLUSION: PFAS exposure may increase the risk of developing COPD, but regular moderate-intensity physical activity can protect individuals from evolving to the disease. However, longitudinal studies are needed to support these preliminary findings.
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Exercício Físico , Fluorocarbonos , Inquéritos Nutricionais , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Masculino , Feminino , Estudos Transversais , Pessoa de Meia-Idade , Fluorocarbonos/sangue , Adulto , Idoso , Exposição Ambiental/efeitos adversos , Fumar/efeitos adversosRESUMO
Celiac disease exhibits a higher prevalence among patients with coronavirus disease 2019. However, the potential influence of COVID-19 on celiac disease remains uncertain. Considering the significant association between gut microbiota alterations, COVID-19 and celiac disease, the two-step Mendelian randomization method was employed to investigate the genetic causality between COVID-19 and celiac disease, with gut microbiota as the potential mediators. We employed the genome-wide association study to select genetic instrumental variables associated with the exposure. Subsequently, these variables were utilized to evaluate the impact of COVID-19 on the risk of celiac disease and its potential influence on gut microbiota. Employing a two-step Mendelian randomization approach enabled the examination of potential causal relationships, encompassing: 1) the effects of COVID-19 infection, hospitalized COVID-19 and critical COVID-19 on the risk of celiac disease; 2) the influence of gut microbiota on celiac disease; and 3) the mediating impact of the gut microbiota between COVID-19 and the risk of celiac disease. Our findings revealed a significant association between critical COVID-19 and an elevated risk of celiac disease (inverse variance weighted [IVW]: P = 0.035). Furthermore, we observed an inverse correlation between critical COVID-19 and the abundance of Victivallaceae (IVW: P = 0.045). Notably, an increased Victivallaceae abundance exhibits a protective effect against the risk of celiac disease (IVW: P = 0.016). In conclusion, our analysis provides genetic evidence supporting the causal connection between critical COVID-19 and lower Victivallaceae abundance, thereby increasing the risk of celiac disease.
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COVID-19 , Doença Celíaca , Microbioma Gastrointestinal , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , SARS-CoV-2 , Doença Celíaca/genética , Doença Celíaca/epidemiologia , COVID-19/epidemiologia , COVID-19/genética , COVID-19/virologia , Humanos , Microbioma Gastrointestinal/genética , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/genéticaRESUMO
Disrupted mitochondrial dynamics and mitophagy contribute to functional deterioration of skeletal muscle (SM) during aging, but the regulatory mechanisms are poorly understood. Our previous study demonstrated that the expression of thyroid hormone receptor α (TRα) decreased significantly in aged mice, suggesting that the alteration of thyroidal elements, especially the decreased TRα, might attenuate local THs action thus to cause the degeneration of SM with aging, while the underlying mechanism remains to be further explored. In this study, decreased expression of myogenic regulators Myf5, MyoD1, mitophagy markers Pink1, LC3II/I, p62, as well as mitochondrial dynamic factors Mfn1 and Opa1, accompanied by increased reactive oxygen species (ROS), showed concomitant changes with reduced TRα expression in aged mice. Further TRα loss- and gain-of-function studies in C2C12 revealed that silencing of TRα not only down-regulated the expression of above-mentioned myogenic regulators, mitophagy markers and mitochondrial dynamic factors, but also led to a significant decrease in mitochondrial activity and maximum respiratory capacity, as well as more mitochondrial ROS and damaged mitochondria. Notedly, overexpression of TRα could up-regulate the expression of those myogenic regulators, mitophagy markers and mitochondrial dynamic factors, meanwhile also led to an increase in mitochondrial activity and number. These results confirmed that TRα could concertedly regulate mitochondrial dynamics, autophagy, and activity, and myogenic regulators rhythmically altered with TRα expression. Summarily, these results suggested that the decline of TRα might cause the degeneration of SM with aging by regulating mitochondrial dynamics, mitophagy and myogenesis.
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Mitocôndrias , Músculo Esquelético , Sarcopenia , Receptores alfa dos Hormônios Tireóideos , Animais , Camundongos , Envelhecimento/metabolismo , Linhagem Celular , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/patologia , Dinâmica Mitocondrial , Mitofagia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Espécies Reativas de Oxigênio/metabolismo , Sarcopenia/metabolismo , Sarcopenia/patologia , Receptores alfa dos Hormônios Tireóideos/genética , Receptores alfa dos Hormônios Tireóideos/metabolismoRESUMO
In the context of exercise psychology, the mediating relationship between peer support, self-efficacy and self-regulation, and adolescents' exercise adherence was to be explored. METHODS: A questionnaire was distributed among 2200 teenagers from twelve middle schools in Shanghai. The "process" program in SPSS and the bootstrap method were applied to construct and analyze the direct and indirect effects of peer support on adolescents' exercise adherence. RESULTS: Peer support directly affected adolescents' exercise adherence (ß = 0.135, p < 0.001, effect size of 59%) and self-efficacy (ß = 0.493, p < 0.001, effect size accounted for 42%), and self-regulation (ß = -0.184, p < 0.001, effect size of 11%) influenced exercise adherence indirectly. In addition, self-efficacy and self-regulation could impose a chain-mediated effect on peer support and exercise adherence (effect size of 6%). CONCLUSION: Peer support could promote adolescents' exercise adherence. Self-efficacy and self-regulation are mediating factors of peer support on exercise adherence in teenagers, self-regulation as well as self-efficacy-imposed chain-mediating effects on peer support and adolescents' exercise adherence.
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Topological semimetals have attracted much attention because of their excellent properties, such as ultra-high speed, low energy consumption quantum transport, and negative reluctance. Searching materials with topological semimetallic properties has become a new research field for Group-IV materials. Herein, using first-principles calculations and tight-binding modeling, we proposed a topological nodal-line semimetal ABW-Ge4 when spin-orbit coupling (SOC) is ignored, which is composed of pure germanium atoms in a zeolite framework ABW. It holds excellent dynamic and thermal stability. In its electronic band structure, there exists a stable Dirac linear band crossing near the Fermi energy level, which forms a closed ring in the kx = 0 plane of the Brillouin zone (BZ). Our symmetry analysis reveals that the nodal ring is protected by Mx mirror symmetry. Furthermore, by examining the slope index in all possible k paths through the considered Dirac point, we find that the band dispersion near the Dirac point is greatly anisotropic. In some direction, the Fermi velocity is even larger than that of graphene, being promising for the future ultra-high speed device. When spin-orbit coupling is included, the nodal line is gapped and the system becomes a topological insulator with topological invariants Z2 = 1. Our findings not only identify a new Ge allotrope but also establish a promising topological material in Group-IV materials, which may have the desirable compatibility with the traditional semiconductor industry.
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Two-dimensional ferromagnetic (FM) half-metals are highly desirable for the development of multifunctional spintronic nano-devices due to their 100% spin polarization and possible interesting single-spin electronic states. Herein, using first-principles calculations based on density functional theory (DFT) with the Perdew-Burke-Ernzerhof (PBE) functional, we demonstrate that the MnNCl monolayer is a promising FM half-metal for spintronics. Specifically, we systematically investigated its mechanical, magnetic, and electronic properties. The results reveal that the MnNCl monolayer has superb mechanic, dynamic, and thermal (ab initio molecular dynamics (AIMD) simulation at 900 K) stability. More importantly, its intrinsic FM ground state has a large magnetic moment (6.16 µB), a large magnet anisotropy energy (184.5 µeV), an ultra-high Curie temperature (952 K), and a wide direct band gap (3.10 eV) in the spin-down channel. Furthermore, by applying biaxial strain, the MnNCl monolayer can still maintain its half-metallic properties and shows an enhancement of magnetic properties. These findings establish a promising new two-dimensional (2D) magnetic half-metal material, which should expand the library of 2D magnetic materials.
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Macrophage polarization plays an important role in asthma. Nuclear receptor corepressor 1 (NCOR1) plays an important role in metabolic and cardiovascular diseases by regulating the function of macrophages. The aim of this research was to examine the role and mechanism of macrophage NCOR1 in the development of asthma. We used ovalbumin (OVA) to induce macrophage NCOR1-deficient mice for asthma formation. Our results revealed that macrophage NCOR1 deficiency markedly enhanced allergic airway inflammation. In addition, NCOR1 deficiency in macrophages was found to enhance M2 polarization. Mechanistic studies suggested that NCOR1 promoted macrophage polarization by interacting with PPARγ, contributing to the pathogenesis of asthma. In conclusion, macrophage NCOR1 deficiency promoted the regulation of M2 programming by enhancing PPARγ expression to exacerbate asthma. Macrophage NCOR1 might be a potential target for the treatment of asthma.
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The current investigation focuses on the stability of the magnesium oxide-based cementitious system under the action of sulfate attack and the dry-wet cycle. The phase change in the magnesium oxide-based cementitious system was quantitatively analyzed by X-ray diffraction, combined with thermogravimetry/derivative thermogravimetry and scanning electron microscope, to explore its erosion behavior under an erosion environment. The results revealed that, in the fully reactive magnesium oxide-based cementitious system under the environment of high concentration sulfate erosion, there was only magnesium silicate hydrate gel formation and no other phase; however, the reaction process of the incomplete magnesium oxide-based cementitious system was delayed, but not inhibited, by the environment of high-concentration sulfate, and it tended to turn completely into a magnesium silicate hydrate gel. The magnesium silicate hydrate sample outperformed the cement sample, in terms of stability in a high-concentration sulfate erosion environment, but it tended to degrade considerably more rapidly, and to a greater extent, than Portland cement, in both dry and wet sulfate cycle environments.
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BACKGROUND AND OBJECTIVE: Deep learning models often suffer from performance degradations when deployed in real clinical environments due to appearance shifts between training and testing images. Most extant methods use training-time adaptation, which almost require target domain samples in the training phase. However, these solutions are limited by the training process and cannot guarantee the accurate prediction of test samples with unforeseen appearance shifts. Further, it is impractical to collect target samples in advance. In this paper, we provide a general method of making existing segmentation models robust to samples with unknown appearance shifts when deployed in daily clinical practice. METHODS: Our proposed test-time bi-directional adaptation framework combines two complementary strategies. First, our image-to-model (I2M) adaptation strategy adapts appearance-agnostic test images to the learned segmentation model using a novel plug-and-play statistical alignment style transfer module during testing. Second, our model-to-image (M2I) adaptation strategy adapts the learned segmentation model to test images with unknown appearance shifts. This strategy applies an augmented self-supervised learning module to fine-tune the learned model with proxy labels that it generates. This innovative procedure can be adaptively constrained using our novel proxy consistency criterion. This complementary I2M and M2I framework demonstrably achieves robust segmentation against unknown appearance shifts using existing deep-learning models. RESULTS: Extensive experiments on 10 datasets containing fetal ultrasound, chest X-ray, and retinal fundus images demonstrate that our proposed method achieves promising robustness and efficiency in segmenting images with unknown appearance shifts. CONCLUSIONS: To address the appearance shift problem in clinically acquired medical images, we provide robust segmentation by using two complementary strategies. Our solution is general and amenable for deployment in clinical settings.