Fig 24 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Scalar representation of two-dimensional vectors. A: A representation of the directions vectors, where red and green indicate the direction of planar vectors, and blue indicates vertical pixels. B: The grey image generated from smoothing the nuclear counts present in the vertical pixels. C: The grey image generated from the planar vectors represented in A. Scale bars represent 1 mm. https://doi.org/10.1371/journal.pone.0173404.g024
Source publication
Background
The fibrous structure of the myometrium has previously been characterised at high resolutions in small tissue samples (< 100 mm³) and at low resolutions (∼500 μm per voxel edge) in whole-organ reconstructions. However, no high-resolution visualisation of the myometrium at the organ level has previously been attained.
Methods and results...
Similar publications
![Figure 1. The pipelined processor model with 7 stages: [IF1] A 32-bit...](publication/335943107/figure/fig1/AS:805210482020352@1568988547824/The-pipelined-processor-model-with-7-stages-IF1-A-32-bit-instruction-is-fetched-from_Q320.jpg)
Spectre and Meltdown attacks in modern microprocessors represent a new class of attacks that have been difficult to deal with. They underline vulnerabilities in hardware design that have been going unnoticed for years. This shows the weakness of the state-of-the-art verification process and design practices. These attacks are OS-independent, and th...
This paper makes the case for a single-ISA heterogeneous computing platform, AISC, where each compute engine (be it a core or an accelerator) supports a different subset of the very same ISA. An ISA subset may not be functionally complete, but the union of the (per compute engine) subsets renders a functionally complete platform-wide single ISA. Ta...
The growing security threat of microarchitectural attacks underlines the importance of robust security sensors and detection mechanisms at the hardware level. While there are studies on runtime detection of cache attacks, a generic model to consider the broad range of existing and future attacks is missing. Unfortunately, previous approaches only c...
We have recently revealed significant differences in microarchitectural properties (i.e. global and local morphometries) and mechanical properties between rheumatoid arthritis (RA), osteoarthritis (OA) and osteoporosis (OP) in cancellous bones. This study compared these properties with those of ageing controls by matching bone volume fraction (BV/T...
Internet-of-Things end-nodes demand low power processing platforms characterized by heterogeneous dedicated units, controlled by a processor core running multiple control threads. Such architecture scheme fits one of the main target application domain of the RISC-V instruction set. We present an open-source processing core compliant with RISC-V on...
Citations
... O miométrio, a camada mais espessa e responsável por aproximadamente 90% da massa muscular uterina (Martini et al., 2015), é considerado o principal responsável pela resposta mecânica do útero. Conforme apresentado em diversos estudos, esse tecido possui comportamento anisotrópico, uma vez que é constituído por músculo liso e este se organiza em fascículos de fibras (Lutton et al., 2017;Myers et al., 2017;Fang et al., 2021). Além disso, também é comum na literatura considerar que o material do útero tem comportamento incompressível (Deyer et al., 2000;Gabella et al., 2021). ...
O parto prematuro, grave problema de saúde pública, afeta um em cada dez bebês globalmente. A distensão patológica do útero pode impor uma tensão à parede uterina capaz de desencadear contrações e, assim, levar ao parto prematuro. Apesar do crescente uso de modelos computacionais para estudos relacionados à gravidez, a falta de dados experimentais e questões éticas limitam os estudos sobre as propriedades mecânicas do útero durante a gestação. Este trabalho apresenta um estudo computacional do crescimento uterino durante a segunda metade da gestação. O modelo geométrico representa o corpo uterino e foi obtido a partir de elipsóides truncados. O modelo constitutivo utilizado é anisotrópico e o tecido foi considerado incompressível. Nessa abordagem, a simulação foi realizada aplicando uma pressão intrauterina e condições de contorno simplificadas. Os resultados obtidos nas simulações mostram a evolução e deformação do útero com o aumento da pressão intrauterina.
... Previous studies using both DT-MRI [27] and histological processing have revealed organizational structure on the centimeter scale. Lutton, et al. were the first to do in-depth 3-D collagen fiber modeling of a human uterus specimen [28]. They used image processing of histology slides to create a 3-D model from a single tissue wedge. ...
... SMCs can be further characterized as either uterine smooth muscle (USM) or vascular smooth muscle (VSM) which are phenotypically different and vary in their presentation based on the presence of vessels and arteries [5]. Histological sectioning suggests that in general SMCs are also aligned structures and well correlated with collagen alignment [28]. This heterogeneity had a minimal effect on the accuracy of our 3-D fiber processing method because both quantification tools, the Radon method and the gradient method, inherently detect brighter image features which correspond with the collagen fibers. ...
... Despite these limitations, the proposed method offers significant advantages over previous methodologies for modeling the 3-D architecture of human uterine tissue. Lutton, et al. used histological processing to model a single NP human uterus 7 cm x 3 cm x 0.35 cm tissue block and create the highest resolution model produced over a multi-centimeter length scale [28]. OCT provides micron resolution images similar to histology and requires significantly less resources to image the same volume of tissue. ...
Automatic quantification and visualization of 3-D collagen fiber architecture using Optical Coherence Tomography (OCT) has previously relied on polarization information and/or prior knowledge of tissue-specific fiber architecture. This study explores image processing, enhancement, segmentation, and detection algorithms to map 3-D collagen fiber architecture from OCT images alone. 3-D fiber mapping, histogram analysis, and 3-D tractography revealed fiber groupings and macro-organization previously unseen in uterine tissue samples. We applied our method on centimeter-scale mosaic OCT volumes of uterine tissue blocks from pregnant and non-pregnant specimens revealing a complex, patient-specific network of fibrous collagen and myocyte bundles.
... Thus, in pregnancy, it may be that implantation and placentation create stimulus hot spots that under the right conditions at term can spread widely to initiate organ-wide excitation. Currently, the situation in the human uterus is unknown but the existence of substantial multiple fibers that traverse from deep in the junctional zone out into the main body of the uterus [4 ] suggest that a fruitful area of future research maybe to understand whether such placental/ myometrial connections exist here too. The prediction would be that there are would be multiple detectable excitation points but that there would be a bias towards the hemisphere of the uterus that harbors the placenta. ...
Contractions of the uterus at term are controlled primarily by the spread of electrical activity throughout the connected structures of myometrial smooth muscle. Substantial progress has been made in measuring bioelectrical signals from the uterus using both electromyography and magnetomyography as a diagnostic for the onset of labor. In this review we survey the current progress of non-invasive measurement of electrical uterine signals and consider what recent advances in our knowledge of the underlying structure of the myometrium mean for their interpretation. It is likely that combining structural knowledge with both MMG and EMG activity will lead to further advances in diagnostic potential.
... Nearer to the cervical canal, the deep fibres form a circular 'cuff' (red in Figure 2(c)), whereas the superficial fibres appear to run in various directions. 7,8 The ability to map the three-dimensional microarchitecture of the myometrial tissue means that we can use simulations to work out the consequences at the whole-organ level of any phenomena that we observe (and may be able to represent in the mathematical form) at the molecular and cellular levels. Thus, in silico reconstruction of histological data forms a bridge between quite disparate levels of biological organisation. ...
... Colour intensity is proportional to nuclear density. Source: Adapted from Lutton et al. 8 labour, secretion of oxytocin occurs as part of the Ferguson reflex ( Figure 3), a positive feedback loop by which contraction of the uterus exerts pressure on the cervix, stimulating sensory neurones that drive secretion by the pituitary gland. 4 This in turn increases the force and frequency of contractions, leading to increased signalling. ...
... The first messenger oxytocin (1) binds to the oxytocin receptor (2), which activates PLC via the activated alpha subunit of the G-protein (3); PLC then cleaves PIP 2 into DAG and IP 3 (4); DAG activates PKC (5), which leads to closure of the BK potassium channel (6), whereas IP 3 binds its receptor in the membrane of the sarcoplasmic reticulum (7), where the majority of intracellular calcium is stored. This interaction leads to a flow of calcium from these stores into the cytoplasm (8), which activates an anionic conductance (9). The changes in potassium and anion conductance alter the membrane potential, thus activating voltage-gated calcium channels, through which extracellular calcium can now enter the cell (10). ...
Pregnancy can be accompanied by serious health risks to mother and child, such as pre-eclampsia, premature birth and postpartum haemorrhage. Understanding of the normal physiology of uterine function is essential to an improved management of such risks. Here we focus on the physiology of the smooth muscle fibres which make up the bulk of the uterine wall and which generate the forceful contractions that accompany parturition. We survey computational methods that integrate mathematical modelling with data analysis and thereby aid the discovery of new therapeutic targets that, according to clinical needs, can be manipulated to either stop contractions or cause the uterine wall muscle to become active.
... To shed light on the processes underlying activation in the rat myometrium, we established a three-step procedure that combines isochronal analysis of multi-electrode recordings with scans of histological slides of the same tissue specimens and automated image processing based on detection of cell nuclei, followed by 3D tissue reconstruction. This analysis enabled the correlation of the kinematics of reconstructed wave fronts of electrical activity propagating along the myometrium with a detailed reconstruction of tissue micro-architecture, at an unprecedented resolution level of 10 μm for an entire organ measuring approximately 5 cm in length (Lutton et al. 2017). Using this strategy, we identified a defined histological structure in which electrical potentials are triggered by the integration of fetal and maternal stimuli, the 'myometrial-placental pacemaker zone' (MPPZ). ...
... Methods for serial sectioning of the tissue, image registration and identification of nuclei in the histological slides were described previously (Lutton et al. 2017). Briefly, the pinned tissue described above was fixed in formalin, embedded in paraffin and sliced into serial sections 5 μm thick. ...
... These slides were stained with haematoxylin and eosin to identify the nuclei in the tissue. In each slide the nuclei of all cell types were automatically identified and the position, size and orientation were recorded (Lutton et al. 2017). In particular, the sizes and the orientation of the nuclei were recorded as the angle between the x-axis and the major axis of the nucleus. ...
Key points:
Coordinated contraction of the uterine smooth muscle is essential to parturition. Histologically and physiologically defined pacemaker structures have not been identified in uterine smooth muscle. Here we report combined electrophysiological and histological evidence of zones associated with pacemaker activity in the rat myometrium. Our method relies crucially on the integration of histological and electrophysiological data in an in silico three-dimensional reconstruction of the rat myometrium at 10 μm resolution. We find that myometrial/placental pacemaking zones are closely related with placental sites and the area of disruptive myometrial remodelling surrounding such sites. If analogues of the myometrial/placental pacemaking zone are present in the human, defining their histology and physiology will be important steps towards treatment of pre-term birth, pre-eclampsia, and postpartum haemorrhage.
Abstract:
Coordinated uterine contractions are essential for delivering viable offspring in mammals. In contrast to other visceral smooth muscles, it is not known where excitation within the uterus is initiated, and no defined pacemaking region has hitherto been identified. Using multi-electrode array recordings and high-resolution computational reconstruction of the three-dimensional micro-structure of late pregnant rat uterus, we demonstrate that electrical potentials are initiated in distinct structures within the placental bed of individual implantation sites. These previously unidentified structures represent modified smooth muscle bundles that are derived from bridges between the longitudinal and circular layers. Coordinated implantation and encapsulation by invading trophoblast give rise to isolated placental/myometrial interface bundles that directly connect to the overlying longitudinal smooth muscle layer. Taken together, these observations imply that the anatomical structure of the uterus, combined with site-specific implantation, gives rise to emergent patterns of electrical activity that drive effective contractility during parturition.
... In rodents, this general structure is well described, and is patterned during early post-natal 37 development [4]. In silico tissue reconstruction visualises and charts 3-dimensional fibrous 38 structure at high resolution [30], allowing us to discover novel anatomical features of the 39 myometrium of functional significance. Detailed analysis revealed bridge-like structures that 40 formed direct connections between the longitudinal and circular layers of the myometrium 41 2/32 certified by peer review) ...
... 13 To shed light on the processes underlying activation in the rat myometrium, we established 14 a three-step procedure that combines isochronal analysis of multi-electrode recordings with 15 scans of histological slides of the same tissue specimens and automated image processing based 16 on detection of cell nuclei, followed by 3D tissue reconstruction. This analysis enabled the 17 correlation of the kinematics of reconstructed wavefronts of electrical activity propagating along 18 the myometrium with a detailed reconstruction of tissue microarchitecture, at an unprecedented 19 resolution level of 10 µm for an entire organ measuring ∼5 cm in length [30]. Using this strategy, 20 we identified a defined histological structure in which electrical potentials are triggered by the 21 integration of fetal and maternal stimuli, the "myometrial-placental pacemaker zone" (MPPZ). ...
... In order to correlate electrical activity with anatomical structure, we first recorded electrical 24 potentials from the serosal surface of rat myometrium as described previously [28]. After 25 recording three representative one-minute time series of spontaneous activity per preparation, 26 each taken from a different animal, the tissues were processed to capture the 3-dimensional 27 histological microarchitecture as described previously [30]. Histological structure and electrical 28 activity were subsequently collated to identify the anatomical sites where electrical excitation 29 originates (Fig. 1). ...
Coordinated uterine contractions at the end of gestation are essential for delivering viable offspring in mammals. Contractions are initiated by an electrical signal at the plasma membrane of uterine muscle cells, leading to voltage-dependent calcium entry, and subsequent activation of the intracellular contractile machinery. In contrast to other visceral smooth muscles, it is not known where excitation within the uterus is initiated, and no defined pacemaking region has hitherto been identified. Using a combination of multi-electrode array recordings and high-resolution computational reconstruction of the three-dimensional micro-structure of late pregnant rat uterus, we demonstrate that electrical potentials are initiated in distinct structures within the placental bed of individual implantation sites. These previously unidentified structures represent modified smooth muscle bundles that are derived from bridges between the longitudinal and circular layers. Coordinated implantation and encapsulation by invading trophoblast give rise to isolated placental/myometrial interface bundles that directly connect to the overlying longitudinal smooth muscle layer. Furthermore, the numerous bridge structures co-localise with the vascular network located between the longitudinal and circular layers. Taken together, these observations imply that the anatomical structure of the uterus, combined with site-specific implantation, gives rise to emergent patterns of electrical activity that drive effective contractility during parturition. The identification of the pacemaking zones of the uterus has important consequences for the treatment of disorders of parturition such as preterm labor, postpartum hemorrhage and uterine dystocia.
Birthing mechanics are poorly understood, though many injuries during childbirth are mechanical, like fetal and maternal tissue damage. Several biomechanical simulation models of parturition have been proposed to investigate birth, but many do not include the uterus. Additionally, most solid models rely on segmenting anatomical structures from clinical images to generate patient geometry, which can be time-consuming. This work presents two new parametric solid modeling methods for generating patient-specific, at-term uterine three-dimensional geometry. Building from an established method of modeling the sagittal uterine shape, this work improves the uterine coronal shape, especially where the fetal head joins the lower uterine wall. Solid models of the uterus and cervix were built from five at-term patients' magnetic resonance imaging (MRI) sets. Using anatomy measurements from models segmented from MRI, two parametric models were created - one that employs an averaged coronal uterine shape and one with multiple axial measurements of the coronal uterus. Through finite element analysis, the two new parametric methods were compared to the MRI-segmented high-fidelity method and a previously published elliptical low-fidelity method. A clear improvement in the at-term uterine shape was found using the two new parametric methods, and agreement in principal Lagrange strain directions was observed across all modeling methods. These methods provide an effective and efficient way to generate patient-specific maternal uterine anatomy, advancing possibilities for future research in computational birthing biomechanics.
Organ-level models are used to describe how cellular and tissue-level contractions coalesce into clinically observable uterine contractions. More importantly, these models provide a framework for evaluating the many different contraction patterns observed in laboring patients, ideally offering insight into the pitfalls of currently available recording modalities and suggesting new directions for improving recording and interpretation of uterine contractions. Early models proposed wave-like propagation of bioelectrical activity as the sole mechanism for recruiting the myometrium to participate in the contraction and increase contraction strength. However, as these models were tested, the results consistently revealed that sequentially propagating waves do not travel long distances and do not encompass the gravid uterus. To resolve this discrepancy, a model using 2 mechanisms, or a "dual model," for organ-level signaling has been proposed. In the dual model, the myometrium is recruited by action potentials that propagate wave-like as far as 10 cm. At longer distances, the myometrium is recruited by a mechanotransduction mechanism that is triggered by rising intrauterine pressure. In this review, we present the influential models of uterine function, highlighting their main features and inconsistencies, and detail the role of intrauterine pressure in signaling and cervical dilation. Clinical correlations demonstrate the application of organ-level models. The potential to improve the recording and clinical interpretation of uterine contractions when evaluating labor is discussed, with emphasis on uterine electromyography. Finally, 7 questions are posed to help guide future investigations on organ-level signaling mechanisms.
We address advances in the understanding of myometrial physiology, focusing on excitation and the effects of gestation on ion channels and their relevance to labor. This review moves through pioneering studies to exciting new findings. We begin with the myometrium and its myocytes and describe how excitation might initiate and spread in this myogenic smooth muscle. We then review each of the ion channels in the myometrium: L- and T-type Ca ²⁺ channels, K ATP (Kir6) channels, voltage-dependent K channels (Kv4, Kv7, and Kv11), twin-pore domain K channels (TASK, TREK), inward rectifier Kir7.1, Ca ²⁺ -activated K ⁺ channels with large (KCNMA1, Slo1), small (KCNN1–3), and intermediate (KCNN4) conductance, Na-activated K channels (Slo2), voltage-gated (SCN) Na ⁺ and Na ⁺ leak channels, nonselective (NALCN) channels, the Na K-ATPase, and hyperpolarization-activated cation channels. We finish by assessing how three key hormones— oxytocin, estrogen, and progesterone—modulate and integrate excitability throughout gestation.
Expected final online publication date for the Annual Review of Physiology, Volume 83 is February 10, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Human uterus specimens from five patients were imaged using SD-OCT and analyzed using our 3-D collagen fiber modeling algorithm. This method provides the first 3-D framework for quantitative comparison of uterine specimens with different parity.
