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Cell Feb 2023Axial development of mammals involves coordinated morphogenetic events, including axial elongation, somitogenesis, and neural tube formation. To gain insight into the...
Axial development of mammals involves coordinated morphogenetic events, including axial elongation, somitogenesis, and neural tube formation. To gain insight into the signals controlling the dynamics of human axial morphogenesis, we generated axially elongating organoids by inducing anteroposterior symmetry breaking of spatially coupled epithelial cysts derived from human pluripotent stem cells. Each organoid was composed of a neural tube flanked by presomitic mesoderm sequentially segmented into somites. Periodic activation of the somite differentiation gene MESP2 coincided in space and time with anteriorly traveling segmentation clock waves in the presomitic mesoderm of the organoids, recapitulating critical aspects of somitogenesis. Timed perturbations demonstrated that FGF and WNT signaling play distinct roles in axial elongation and somitogenesis, and that FGF signaling gradients drive segmentation clock waves. By generating and perturbing organoids that robustly recapitulate the architecture of multiple axial tissues in human embryos, this work offers a means to dissect mechanisms underlying human embryogenesis.
Topics: Animals; Humans; Body Patterning; Embryonic Development; Gene Expression Regulation, Developmental; Mammals; Mesoderm; Morphogenesis; Somites; Wnt Signaling Pathway; Organoids
PubMed: 36657441
DOI: 10.1016/j.cell.2022.12.042 -
Ophthalmic & Physiological Optics : the... May 2021Both emmetropic and myopic eyes elongate throughout childhood. The goals of this study were to compare axial elongation among untreated progressing myopes, progressing... (Comparative Study)
Comparative Study Randomized Controlled Trial
PURPOSE
Both emmetropic and myopic eyes elongate throughout childhood. The goals of this study were to compare axial elongation among untreated progressing myopes, progressing myopes treated with a myopia control contact lens and emmetropes, in order to place axial elongation in the context of normal eye growth in emmetropic children, and to consider whether normal physiological eye growth places limits on what might be achieved with myopia control.
METHODS
Axial elongation data were taken from the 3-year randomised clinical trial of a myopia control dual-focus (MiSight® 1 day) contact lens. These were compared with data for myopic and emmetropic children in two large cohort studies: the Orinda Longitudinal Study of Myopia (OLSM) and the Singapore Cohort Study of the Risk Factors for Myopia (SCORM). Each study's published equations were used to calculate annual axial elongation. Four virtual cohorts-myopic and emmetropic for each model-were created, each with the same age distribution as the MiSight clinical trial subjects and the predicted cumulative elongation calculated at years 1, 2 and 3 for myopes and emmetropes using both the OLSM and SCORM models.
RESULTS
The untreated control myopes in the MiSight clinical trial showed mean axial elongation over 3 years (0.62 mm) similar to the virtual cohorts based on the OLSM (0.70 mm) and SCORM (0.65 mm) models. The predicted 3-year axial elongation for the virtual cohorts of emmetropes was 0.24 mm for both the OLSM and SCORM models-similar to the mean 3-year elongation in MiSight-treated myopes (0.30 mm).
CONCLUSIONS
The 3-year elongation in MiSight-treated myopes approached that of virtual cohorts of emmetropes with the same age distribution. It is hypothesised that myopic axial elongation is superimposed on an underlying physiological axial elongation observed in emmetropic eyes, which reflects increases in body stature. We speculate that optically based myopia control treatments may minimise the myopic axial elongation but retain the underlying physiological elongation observed in emmetropic eyes.
Topics: Adolescent; Axial Length, Eye; Child; Disease Management; Female; Follow-Up Studies; Humans; Male; Myopia; Time Factors
PubMed: 33951213
DOI: 10.1111/opo.12812 -
Cell Feb 2023The human embryo breaks symmetry to form the anterior-posterior axis of the body. As the embryo elongates along this axis, progenitors in the tail bud give rise to...
The human embryo breaks symmetry to form the anterior-posterior axis of the body. As the embryo elongates along this axis, progenitors in the tail bud give rise to tissues that generate spinal cord, skeleton, and musculature. This raises the question of how the embryo achieves axial elongation and patterning. While ethics necessitate in vitro studies, the variability of organoid systems has hindered mechanistic insights. Here, we developed a bioengineering and machine learning framework that optimizes organoid symmetry breaking by tuning their spatial coupling. This framework enabled reproducible generation of axially elongating organoids, each possessing a tail bud and neural tube. We discovered that an excitable system composed of WNT/FGF signaling drives elongation by inducing a neuromesodermal progenitor-like signaling center. We discovered that instabilities in the excitable system are suppressed by secreted WNT inhibitors. Absence of these inhibitors led to ectopic tail buds and branches. Our results identify mechanisms governing stable human axial elongation.
Topics: Humans; Body Patterning; Mesoderm; Wnt Signaling Pathway; Embryo, Mammalian; Organoids
PubMed: 36657443
DOI: 10.1016/j.cell.2022.12.043 -
BMC Musculoskeletal Disorders Mar 2022Optimal treatment of nonradiographic axial spondyloarthritis depends on accurate and timely diagnosis of the underlying disease; however, patients present with common... (Review)
Review
BACKGROUND
Optimal treatment of nonradiographic axial spondyloarthritis depends on accurate and timely diagnosis of the underlying disease; however, patients present with common symptoms that, in the absence of radiographic changes, may confound diagnosis.
METHODS AND FINDINGS
In this narrative review, a PubMed literature search was conducted through January 2021, with no date limits, to identify English-language publications discussing classification of nonradiographic axial spondyloarthritis, with an emphasis on clinical features and presentation, differential diagnoses, and mimics of disease. This review describes the epidemiology, clinical features, and burden of disease of nonradiographic axial spondyloarthritis as it relates to the overall axial spondyloarthritis spectrum and discusses mimics and differential diagnoses of nonradiographic axial spondyloarthritis that should be considered when evaluating patients with suspected nonradiographic axial spondyloarthritis in clinical practice.
CONCLUSIONS
Recognition of clinical features of nonradiographic axial spondyloarthritis, along with an understanding of comorbid conditions such as fibromyalgia, allows for differentiation from its mimics. Appropriate diagnosis of nonradiographic axial spondyloarthritis is important for aggressive management of disease to reduce pain, avoid loss of function, and improve quality of life.
Topics: Comorbidity; Diagnosis, Differential; Humans; Non-Radiographic Axial Spondyloarthritis
PubMed: 35279103
DOI: 10.1186/s12891-022-05073-7 -
Optics Express Jun 2020Here we introduce three-dimensional single-shot ptychography (3DSSP). 3DSSP leverages an additional constraint unique to the single-shot geometry to deconvolve multiple...
Here we introduce three-dimensional single-shot ptychography (3DSSP). 3DSSP leverages an additional constraint unique to the single-shot geometry to deconvolve multiple 2D planes of a 3D object. Numeric simulations and analytic calculations demonstrate that 3DSSP reconstructs multiple planes in an extended 3D object with a minimum separation consistent with the depth of field for a conventional microscope. We experimentally demonstrate 3DSSP by reconstructing orthogonal hair strands axially separated by 5 mm. 3DSSP provides a pathway towards volumetric imaging of dynamically evolving systems on ultrafast timescales.
PubMed: 32672178
DOI: 10.1364/OE.395205 -
Chemistry (Weinheim An Der Bergstrasse,... May 2022Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral... (Review)
Review
Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C-C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C-N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C-N axes. The preparation of different families of C-N based atropisomers is then presented from anilides to chiral five- and six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.
Topics: Biological Products; Catalysis; Ligands; Stereoisomerism
PubMed: 35191558
DOI: 10.1002/chem.202104442 -
Eye and Vision (London, England) 2020The goal of this review is to summarize structural and anatomical changes associated with high myopia. (Review)
Review
BACKGROUND
The goal of this review is to summarize structural and anatomical changes associated with high myopia.
MAIN TEXT
Axial elongation in myopic eyes is associated with retinal thinning and a reduced density of retinal pigment epithelium (RPE) cells in the equatorial region. Thickness of the retina and choriocapillaris and RPE cell density in the macula are independent of axial length. Choroidal and scleral thickness decrease with longer axial length in the posterior hemisphere of the eye, most marked at the posterior pole. In any eye region, thickness of Bruch's membrane (BM) is independent of axial length. BM opening, as the inner layer of the optic nerve head layers, is shifted in temporal direction in moderately elongated eyes (axial length <26.5 mm). It leads to an overhanging of BM into the intrapapillary compartment at the nasal optic disc side, and to an absence of BM at the temporal disc border. The lack of BM at the temporal disc side is the histological equivalent of parapapillary gamma zone. Gamma zone is defined as the parapapillary region without BM. In highly myopic eyes (axial length >26.5 mm), BM opening enlarges with longer axial length. It leads to a circular gamma zone. In a parallel manner, the peripapillary scleral flange and the lamina cribrosa get longer and thinner with longer axial length in highly myopic eyes. The elongated peripapillary scleral flange forms the equivalent of parapapillary delta zone, and the elongated lamina cribrosa is the equivalent of the myopic secondary macrodisc. The prevalence of BM defects in the macular region increases with longer axial length in highly myopic eyes. Scleral staphylomas are characterized by marked scleral thinning and spatially correlated BM defects, while thickness and density of the choriocapillaris, RPE and BM do not differ markedly between staphylomatous versus non-staphylomatous eyes in the respective regions.
CONCLUSIONS
High axial myopia is associated with a thinning of the sclera and choroid posteriorly and thinning of the retina and RPE density in the equatorial region, while BM thickness is independent of axial length. The histological changes may point towards BM having a role in the process of axial elongation.
PubMed: 32905133
DOI: 10.1186/s40662-020-00210-6 -
RMD Open Jun 2023Within the spectrum of spondyloarthritides, axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) present with overlapping features. Axial involvement in PsA...
BACKGROUND
Within the spectrum of spondyloarthritides, axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) present with overlapping features. Axial involvement in PsA (axial PsA) is treated according to recommendations for axSpA, as specific studies in axial PsA are scarce. We compared characteristics of patients with axSpA (particularly of patients with axSpA and concomitant psoriasis (pso)) with those of patients with axial PsA.
METHODS
Patients with axSpA and PsA in the Swiss Clinical Quality Management (SCQM) registry were included if information on pso and axial involvement was available. Patients with AxSpA were stratified by axSpA with and without pso (axSpA±pso) and patients with PsA were stratified to axial PsA or strictly peripheral PsA.
RESULTS
Previous or current psoriasis was observed in 479/4489 patients with axSpA (10.7%). Of 2631 patients with PsA, 1153 (43.8%) presented with axial involvement (opinion of the treating rheumatologist). Compared with patients with axSpA+pso, patients with axial PsA were older at symptom onset and at inclusion in SCQM, were less frequently HLA-B27 positive, had back pain less frequently and a higher prevalence of dactylitis and peripheral arthritis. A positive family history of pso or PsA was more frequent in axial PsA, while a positive family history of axSpA was more frequent in patients with axSpA+pso. Disease activity, function and mobility were comparable in axSpA+pso versus axial PsA.
CONCLUSION
Patients with axial PsA differ from patients with axSpA+pso in important demographic and clinical characteristics, and genetically, but present with a comparable disease burden. Treatment studies specifically dedicated to axial PsA seem warranted.
Topics: Humans; Arthritis, Psoriatic; Spondylarthritis; Psoriasis; Axial Spondyloarthritis; Registries
PubMed: 37277211
DOI: 10.1136/rmdopen-2022-002956 -
Heliyon Feb 2023To examine histologic characteristics of macular Bruchś membrane defects (BMD) in axially elongated eyes.
PURPOSE
To examine histologic characteristics of macular Bruchś membrane defects (BMD) in axially elongated eyes.
DESIGN
Histomorphometric study.
METHODS
Using light microscopy, we examined enucleated human globes for BMDs.
RESULTS
In 247 eyes, BMDs were detected in 15 (6.1%) eyes (axial length:27.0-36.0 mm), in 10 of them in the macular region. Prevalence and size of BMDs (mean:1.93 ± 1.62 mm; range:0.22mm-6.24 mm) correlated with longer axial length (OR:1.52; 95%CI:1.19,1.94; P = 0.001) and higher prevalence of scleral staphylomas (OR:16.3; 95%CI:2.67,99.3; P < 0.001). The BMDs were smaller than corresponding gaps in the retinal pigment epithelium (RPE) (1.93 ± 1.62 mm versus 2.61 mm ± 1.73 mm; P = 0.003), and larger than corresponding gaps in the inner nuclear layer (0.43 ± 0.76 mm; P = 0.008) and inner limiting membrane bridges (0.13 ± 0.33 mm; P = 0.001). Choriocapillaris thickness, BM thickness and RPE cell density did not vary (all P > 0.05) between the BDM border and adjacent areas. In the BMD, choriocapillaris and RPE were absent. The sclera was thinner in the BDM area than in adjacent areas (0.28 ± 0.19 mm versus 0.36 ± 0.13 mm; P = 0.006).
CONCLUSIONS
BMDs as hallmarks of myopic macular degeneration are characterized by longer gaps in the RPE and smaller gaps in the outer nuclear layer and inner nuclear layer, by localized scleral thinning, and by a spatial association with scleral staphylomas. Thickness of the choriocapillaris and density of the RPE cell layer, both absent within the BDMs, do not vary between the BMD border and adjacent regions. The results suggest an association between BDMs and absolute scotomas, stretching of the adjacent retinal nerve fiver layer, and an axial elongation-associated stretching effect on BM as etiology of the BDMs.
PubMed: 36793950
DOI: 10.1016/j.heliyon.2023.e13257