scholarly journals Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle

2018 ◽  
Author(s):  
Elizabeth M Sefton ◽  
Mirialys Gallardo ◽  
Gabrielle Kardon
Keyword(s):  
Connective Tissue ◽  
Phrenic Nerve ◽  
Leading Edge ◽  
List Type ◽  
Mammalian Skeletal Muscle ◽  
Coordinated Development ◽  
Developmental Origin ◽  
Muscle Nerve ◽  
Axon Projection ◽  
Thoracic And Abdominal

AbstractThe diaphragm is a mammalian skeletal muscle essential for respiration and for separating the thoracic and abdominal cavities. Development of the diaphragm requires the coordinated development of muscle, muscle connective tissue, tendon, nerves, and vasculature that derive from different embryonic sources. However, defects in diaphragm development are common and the cause of an often deadly birth defect, Congenital Diaphragmatic Hernia (CDH). Here we comprehensively describe the normal developmental origin and complex spatial-temporal relationship between the different developing tissues to form a functional diaphragm using a developmental series of mouse embryos genetically and immunofluorescently labeled and analyzed in whole mount. We find that the earliest developmental events are the emigration of muscle progenitors from cervical somites followed by the projection of phrenic nerve axons from the cervical neural tube. Muscle progenitors and phrenic nerve target the pleuroperitoneal folds (PPFs), transient pyramidal-shaped structures that form between the thoracic and abdominal cavities. Subsequently, the PPFs expand across the surface of the liver to give rise to the muscle connective tissue and central tendon, and the leading edge of their expansion precedes muscle morphogenesis, formation of the vascular network, and outgrowth and branching of the phrenic nerve. Thus development and morphogenesis of the PPFs is critical for diaphragm formation. In addition, our data indicate that the earliest events in diaphragm development are critical for the etiology of CDH and instrumental to the evolution of the diaphragm. CDH initiates prior to E12.5 in mouse and suggests that defects in the early PPF formation or their ability to recruit muscle are an important source of CDH. Also, the recruitment of muscle progenitors from cervical somites to the nascent PPFs is uniquely mammalian and a key developmental innovation essential for the evolution of the muscularized diaphragm.HighlightsDiaphragm development begins with emigration of muscle progenitors from cervical somites.Phrenic nerve axons follow muscle path towards nascent pleuroperitoneal folds (PPFs).PPFs are the target of muscle migration and phrenic nerve axon projectionPPF expansion precedes and likely directs muscle, nerve, and vasculature development.Early defects in PPFs and muscle recruitment are likely a source of CDH.

Fibroblast-derived HGF integrates muscle and nerve development during morphogenesis of the mammalian diaphragm

2021 ◽  
Author(s):  
Elizabeth M. Sefton ◽  
Mirialys Gallardo ◽  
Claire E. Tobin ◽  
Mary P. Colasanto ◽  
Gabrielle Kardon
Keyword(s):  
Connective Tissue ◽  
Phrenic Nerve ◽  
Birth Defect ◽  
Diaphragm Muscle ◽  
Coordinated Development ◽  
Pharmacological Inhibition ◽  
Summary Statement ◽  
The Common ◽  
Nerve Development ◽  
Diaphragmatic Hernias

AbstractThe diaphragm is a domed muscle between the thorax and abdomen essential for breathing in mammals. Diaphragm development requires the coordinated development of muscle, connective tissue, and nerve, which are derived from different embryonic sources. Defects in diaphragm development cause the common and often lethal birth defect, Congenital Diaphragmatic Hernias (CDH). HGF/MET signaling is required for diaphragm muscularization, but the source of HGF and the specific functions of this pathway in muscle progenitors or potentially the phrenic nerve have not been explicitly tested. Using conditional mutagenesis and pharmacological inhibition of MET, we demonstrate that the pleuroperitoneal folds (PPFs), transient embryonic structures that give rise to the connective tissue, are the source of HGF critical for diaphragm muscularization and phrenic nerve primary branching. HGF not only is required for recruitment of muscle progenitors to the diaphragm, but is continuously required for maintenance and motility of the pool of progenitors to enable full muscularization. Thus, the connective tissue fibroblasts and HGF coordinately regulate diaphragm muscularization and innervation. Defects in PPF-derived HGF result in muscleless regions that are susceptible to CDH.Summary StatementFibroblast-derived HGF signals to Met+ muscle progenitors and nerve to control the expansion of diaphragm muscle and primary branching of phrenic nerve axons - structures critical for breathing in mammals.

Some Remarks on Vortex Drag and its Spanwise Distribution in Incompressible Flow

1968 ◽  
Vol 72 (691) ◽  
pp. 623-625 ◽  
Author(s):  
H. C. Garner
Keyword(s):  
Theoretical Data ◽  
Leading Edge ◽  
List Type ◽  
Surface Theory ◽  
Lifting Surface ◽  
Line Theory ◽  
Lifting Line ◽  
Swept Wings ◽  
Lifting Line Theory ◽  
Drag Factor

Summary Theoretical data from lifting-surface theory are presented to illustrate (i) that the vortex drag factor is closely related to the half-wing spanwise centre of pressure on simple planforms without camber or twist, (ii) that lifting-line theory is useless for predicting the spanwise distribution of vortex drag on swept wings, (iii) that recent numerical improvements in lifting-surface theory help to reconcile the concepts of wake energy and leading-edge suction in relation to vortex drag.

Note on the Extension of Evvard’s Method to Wings with Subsonic Leading Edges Moving at Supersonic Speeds

1957 ◽  
Vol 8 (1) ◽  
pp. 87-102 ◽  
Author(s):  
G. J. Hancock
Keyword(s):  
Flat Plate ◽  
Delta Wing ◽  
Leading Edge ◽  
Wing Surface ◽  
List Type ◽  
Pressure Loading ◽  
Supersonic Speed ◽  
Triangular Wing ◽  
Finite Wing ◽  
The Relationship

SummaryEvvard’s technique is applied to the problem of a thin finite wing moving at a supersonic speed when the leading edge is subsonic. It is developed in two methods:—(i) in which the relationship between the pressure loading and the integrals of the downwash over the wing surface is extended as far as possible, and which has to be computed numerically;(ii) in which approximations are made for the upwash velocities in the neighbourhood of the leading edge, resulting in a series of standard integrals for the estimation of the pressure loading.Method (ii) is applied to the pressure loading on a flat plate triangular wing and cropped delta wing, and the application to more general shapes is discussed.

Postural disturbances resulting from unilateral and bilateral diaphragm contractions: a phrenic nerve stimulation study

2014 ◽  
Vol 117 (8) ◽  
pp. 825-832 ◽  
Author(s):  
Alain Hamaoui ◽  
Anna L. Hudson ◽  
Louis Laviolette ◽  
Marie-Cécile Nierat ◽  
Manh-Cuong Do ◽  
...  
Keyword(s):  
Nerve Stimulation ◽  
Phrenic Nerve ◽  
Force Plate ◽  
The Body ◽  
Lateral Acceleration ◽  
Forward Peak ◽  
Phrenic Nerve Stimulation ◽  
Postural Disturbance ◽  
Thoracic And Abdominal ◽  
Phrenic Stimulation

Thoracoabdominal breathing movements are a complex source of postural disturbance, but there are contradictory reports in the literature with inspiration described as having either a backward or a forward disturbing effect. To elucidate the mechanisms underlying this phenomenon, the present study studied the postural disturbance caused by isolated contractions of the diaphragm. Eight male and four female healthy subjects followed an original paradigm of phrenic nerve stimulation (bilateral and unilateral) and “diaphragmatic” voluntary sniff maneuvers in the seated and standing postures. Center of gravity (CG) acceleration was calculated from force plate recordings, and respiratory kinematics were assessed with thoracic and abdominal sensor belts. CG and respiratory signals revealed that, while seated, bilateral phrenic stimulation and sniff maneuvers consistently produced expansion of the abdomen associated with a forward peak of CG acceleration. In the standing posture, the direction of the CG peak was reversed and always directed backward. Unilateral phrenic stimulation induced an additional medial-lateral acceleration of the CG, directed toward the nonactive side while seated, but in the opposite direction while standing. These results suggest that isolated diaphragmatic contractions produce a constant disturbing pattern for a given posture, but with opposite effects between standing and seated postures. This could be related to the different biomechanical configuration of the body in each posture, corresponding to distinct kinematic patterns of the osteoarticular chain. In addition, the lateral component of the CG acceleration induced by unilateral diaphragm contractions could be clinically relevant in patients with hemidiaphragm paralysis.

scholarly journals Fatigue in mammalian skeletal muscle stimulated under computer control

2001 ◽  
Vol 90 (1) ◽  
pp. 189-197 ◽  
Author(s):  
A. K. Wise ◽  
D. L. Morgan ◽  
J. E. Gregory ◽  
U. Proske
Keyword(s):  
Human Subjects ◽  
Computer Control ◽  
Limited Range ◽  
Medial Gastrocnemius ◽  
Mammalian Skeletal Muscle ◽  
Muscle Nerve ◽  
Computer Controlled ◽  
Postural Support ◽  
Medial Gastrocnemius Muscle ◽  
Stimulation Of

Functional electrical stimulation (FES) is used to provide paralyzed human subjects with postural support and a limited range of movements. Problems encountered with FES include jerky movements from tension oscillations during stimulation and rapid muscle fatigue. In this paper, we report experiments on anesthetized cats that test a new, computer-controlled method of stimulation of the muscle nerve supply, distributed across several inputs, which reduces these problems. After 5 min of continuous, distributed stimulation of the medial gastrocnemius muscle at 6 pulses per second (pps) across 6 channels, tension fell to 55.9 ± 3.9% (SE) of its original value. In comparison, after 5 min of synchronous stimulation of one muscle portion at 36 pps, tension fell to 11 ± 3.7%. At higher stimulation rates, 10 pps per channel (distributed) and 60 pps (synchronous), the differences in fatigue were even greater. Similar results were obtained when an intermittent, rather than a continuous, stimulation protocol was used. These findings indicate that distributed stimulation has important advantages over other methods for applications such as FES.

scholarly journals Density and distribution of α-bungarotoxin-binding sites in postsynaptic structures of regenerated rat skeletal muscle

1981 ◽  
Vol 88 (2) ◽  
pp. 338-345 ◽  
Author(s):  
D Bader
Keyword(s):  
Skeletal Muscle ◽  
Connective Tissue ◽  
Morphometric Analysis ◽  
Binding Sites ◽  
Acetylcholine Receptors ◽  
Mammalian Skeletal Muscle ◽  
Rat Skeletal Muscle ◽  
Em Autoradiography ◽  
Postsynaptic Differentiation ◽  
Vertebrate Skeletal Muscle

Acetylcholine receptors (AChR) are organized in a discrete and predictable fashion in the postsynaptic regions of vertebrate skeletal muscle. When muscle is damaged, nerves and myofibers including muscular elements of the endplate degenerate, but the connective tissue elements survive. Muscle fibers regenerate within the basal lamina of the original myofiber. Postsynaptic differentiation in regenerated mammalian skeletal muscle can occur in different ways: (a) at the site of the original endplate in the presence or absence of the nerve, or (b) at ectopic regions of the regenerated myofiber in the presence of the nerve when the original endplate is not present. The present study used (125)I-α- bungarotoxin ((125)I-α-BuTX) and EM autoradiography to examine the density and distribution of AChR in postsynaptic structures regenerated at the site of the original endplate in the absence of the nerve and at ectopic sites of the myofiber in the presence of the nerve when the original endplate was removed. In regenerated myofibers, the density of α-BuTX-binding sites fell within the range of densities observed in uninjured muscle whether postsynaptic differentiation occurred at the site of the original endplate in the absence of the nerve or at an originally ectopic position of the regenerated myofiber. In addition, the distribution of α-BuTX-binding sites within the regenerated postsynaptic regions closely resembled the distribution of apha-BuTX- binding sites in uninjured muscle. Morphometric analysis was performed on postsynaptic structures formed at the site of the original endplate in the absence of the nerve or at an ectopic position of the regenerated myofiber by interaction of the nerve and muscle. Although variation in the depth of the primary cleft occurred, there was little difference between the overall structure of regenerated postsynaptic structures and that of endplates of uninjured muscles.

scholarly journals SAT0653-HPR COMMUNITY RHEUMATOLOGY SERVICE IN THE UK – WHO BENEFITS THE MOST?

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1285.2-1286
Author(s):  
K. Szabo-Kocsis ◽  
M. Dare
Keyword(s):  
Primary Care ◽  
Connective Tissue ◽  
Waiting Time ◽  
Secondary Care ◽  
List Type ◽  
Ehlers Danlos Syndrome ◽  
Specialist Services ◽  
Wide Range ◽  
Set Up ◽  
The Uk

Background:Community rheumatology (CR) in the UK is a new form of rheumatologic service provision established in the last few years and run by few organisations such as Connect Health Ltd.CR is based on the principle of sharing the management of rheumatologic patients between community service and secondary care aiming to reduce the unreasonable referral flow from primary care to secondary care and to share the care of stable inflammatory patients between the services.In the traditional service model patients are referred by General Practitioners (GP) to the secondary care with a wide spectrum of conditions: from fibromyalgia through soft tissues rheumatisms to inflammatory or connective tissue diseases. Many of these patients will be discharged from the specialist service after their first visit with fibromyalgia, osteoarthritis, chronic pain syndrome or MSK diagnoses. The proportion of these patients versus those who have an inflammatory rheumatologic condition or connective tissue disease (CTD) varies significantly and can contribute to oversaturated specialist rheumatologic services with long waiting time where specialists deal with less relevant cases.Objectives:To determine how CR can improve quality of care and decrease the waiting time for appointment in secondary care rheumatology services. To set standards for referral pathways and measured outcomes of effectiveness in patient care.In the UK the regional Clinical Commissioning Groups would accept a maximum waiting time from the referral until patient treatment of up to 18 weeks and specialist services often breach that limit. This long interval may have a significant negative impact for the care of patients with rheumatological condition, reducing patient satisfaction and/or jeopardize patient safety. The solution to the above problem is the creation of CR service.Methods:Extensive search about the available resources within UK NHS system in regards CR service creation and set up. Web search, literature review in relation to CR in the UKResults:From the research different models of CR can be identified and one of these will be presented in details based on the experience of one of the largest organisation running CR services in the UK (Connect Health Ltd). This service is organised within community care set up and can accept patients referred by the primary care physicians with non-inflammatory symptoms (e.g. osteoarthritis, Ehlers - Danlos Syndrome, fibromyalgia) or PMR or gout. The service also can review stable inflammatory patients who are treated with DMARDs and are transferred from the secondary care service by their consultant. This presentation will demonstrate how CR provides safer, faster and more accessible services to the patients assisting the specialist services and allowing them to concentrate on the inflammatory and CTD patients who need faster access to these services than it is possible now. Particularly the presentation will emphasise on:Patient population coverTeam structure, their experience and trainingReferral criteria and IT set up for multidisciplinary connectionTime interval for appointment and patient feedbackImpact on the secondary care rheumatology serviceCases of misdiagnosis and inappropriate referralsCost effectiveness of the CRChallenges in the CR serviceConclusion:The CR service can be a safe addition to the specialist services taking over significant workload and provide new career opportunities for a wide range of Allied Health Professionals (AHP) for the bigger satisfaction of the patients who can access rheumatology service earlier and easier.Disclosure of Interests:None declared

scholarly journals Cell Mechanics at the Rear Act To Steer the Direction of Cell Migration

2018 ◽  
Author(s):  
Greg M. Allen ◽  
Kun Chun Lee ◽  
Erin L. Barnhart ◽  
Mark A. Tsuchida ◽  
Cyrus A. Wilson ◽  
...  
Keyword(s):  
Computational Model ◽  
Network Flow ◽  
Actin Polymerization ◽  
Myosin Ii ◽  
Leading Edge ◽  
Minor Role ◽  
List Type ◽  
Motile Cells ◽  
Cell Shapes ◽  
A Minor

SummaryMotile cells navigate complex environments by changing their direction of travel, generating left-right asymmetries in their mechanical subsystems to physically turn. Currently little is known about how external directional cues are propagated along the length scale of the whole cell and integrated with its force-generating apparatus to steer migration mechanically. We examine the mechanics of spontaneous cell turning in fish epidermal keratocytes and find that the mechanical asymmetries responsible for turning behavior predominate at the rear of the cell, where there is asymmetric centripetal actin flow. Using experimental perturbations we identify two linked feedback loops connecting myosin II contractility, adhesion strength and actin network flow in turning cells that are sufficient to recreate observed cell shapes and trajectories in a computational model. Surprisingly, asymmetries in actin polymerization at the cell leading edge play only a minor role in the mechanics of cell turning – that is, cells steer from the rear.HighlightsFish keratocytes can migrate with persistent angular velocity, straight or in circles.Asymmetry in protrusion at the leading edge is not sufficient to generate persistent turning.Asymmetries in myosin II contraction, actin flow and adhesion at the cell rear cause turns.Our new computational model of migration predicts observed cell trajectories.

scholarly journals THU0244 3 YEAR FOLLOW UP OF AN AT-RISK CONNECTIVE TISSUE DISEASE COHORT: ANALYSIS OF CLINICAL, GENE EXPRESSION AND FLOW CYTOMETRIC BIOMARKERS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 349.1-349
Author(s):  
S. U. Hassan ◽  
Z. Wigston ◽  
A. Psarras ◽  
K. Dutton ◽  
M. Y. MD Yusof ◽  
...  
Keyword(s):  
At Risk ◽  
Flow Cytometry ◽  
Connective Tissue ◽  
Diagnostic Criteria ◽  
Connective Tissue Disease ◽  
Mean Difference ◽  
List Type ◽  
Clinical Criteria ◽  
Significant Disease

Background:We previously reported results from the first 118 “At-Risk” of autoimmune connective tissue disease (AI-CTD) individuals (i.e. ANA positivity, non-specific symptoms of ≤1 year and treatment naïve). At 1 year, 16% progressed to meet classification criteria for an AI-CTD. This was predicted by high baseline interferon (IFN) Score B and family history of RMD[1].However, some may have progressed at later time points, or had clinically significant disease despite not meeting diagnostic criteria. Longer term outcomes, baseline and follow up flow cytometry biomarkers were never reported.Objectives:(i)Describe detailed analysis of 3-year follow-up data of the At-Risk cohort(ii)Evaluate flow cytometric biomarkers as predictors of these outcomes(iii)Analyse follow up biomarkersMethods:We conducted a prospective observational longitudinal study of At-Risk individuals in Leeds (n=150). Patients were assessed at baseline, then annually for 3 years. Depending on diagnostic criteria and need for therapy, patients were grouped as follows:Absolute non-progressors (no clinical diagnostic criteria)Undifferentiated CTD (U-CTD) (≥1 clinical criteria at baseline persisting at follow-up but not meeting criteria). This group was subdivided into those who required treatment with an immunosuppressant (IS) excluding antimalarials and those who did notYear 1 progressors (meeting criteria for an RMD by 1 year)Late progressors (meeting criteria for AI-CTD beyond 1 year follow-up).Bloods were analysed at baseline and 1 year for two IFN-stimulated gene expression scores previously described[2], monocytes and subsets of B and T cells using flow cytometry. Association between clinical criteria, biomarkers at baseline and long term outcomes were tested using ANOVA.Results:3 year follow up data was available in 147/150 patients. Outcomes were: Absolute non-progressors: 63/147 (43%); U-CTD: 54/147 (37%); Year 1 progressors: 21/147 (14%) [SLE=18; pSS=3]; Late progressors (in years 1-2): 9/147 (6%) [SLE=7; pSS=2]. None progressed or required IS initiation beyond the first 2 years of follow-up. In U-CTD group, 7/54 (13%) were prescribed an IS.This work describes a larger group of 36/147 (24%) At-Risk individuals who developed clinically significant disease (CSD: progressors or need for IS) versus clinically non-significant disease (CNSD: absolute non-progressors or UCTD not needing IS).Analysis of baseline biomarkers between CSD and CNSD confirmed a significant difference in IFN Score B (mean difference -0.74, p = 0.027), but not IFN Score A (mean difference -0.68, p = 0.15). In flow cytometry analysis, there was also a significant difference in percentage monocytes (mean difference -4.09, p = 0.004) but no other subset. Absence of clinical criteria at baseline did not predict clinical outcome, and no one clinical criterion had greater predictive value.In follow up samples we noted a significant reduction in expression of IFN Score B in both groups, regardless of whether they received antimalarials or IS therapy.Conclusion:Here we report findings of a larger group of 24% At-Risk individuals who developed CSD (progressors and patients who did not meet criteria but needed IS therapy). These results provide a more complex picture of IFN activity in the initiation of SLE than previously suspected. First, we confirm that a specific subset of ISGs rather than a classic IFN signature predicts progression. Second, the reduction in IFN-Score-B in both groups suggests that IFN Score B activity is a transient phenomenon, playing a greater role in disease initiation than in disease maintenance.References:[1]Md Yusof MY, Psarras A, El-Sherbiny YM, et al. Prediction of autoimmune connective tissue disease in an at-risk cohort: prognostic value of a novel two-score system for interferon status. Ann Rheum Dis. 2018 Oct;77(10):1432-1439.[2]El-Sherbiny YM, Psarras A, Md Yusof MY, et al. A novel two score system for interferon status segregates autoimmune diseases and correlateswith clinical features. Sci Rep. 2018 Apr 11;8(1):5793.Disclosure of Interests:Sabih-Ul Hassan: None declared, Zoe Wigston: None declared, Antonios Psarras: None declared, Katie Dutton: None declared, Md Yuzaiful Md Yusof: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK

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