Differential Expression of Fibulin Family Proteins in Mechanically Strong vs. Weak Fetal Membrane Fragments

2007 ◽  
Author(s):  
John J. Moore ◽  
Robert M. Moore ◽  
Deepak Kumar ◽  
Joseph M. Mansour ◽  
Brian M. Mercer ◽  
...  
Keyword(s):  
Physiological Mechanism ◽  
Biomechanical Properties ◽  
Fetal Membrane ◽  
Weak Zone ◽  
Mortality And Morbidity ◽  
Collagen Remodeling ◽  
Uterine Contractions ◽  
Sentinel Event ◽  
Specific Proteins ◽  
Near Term

Untimely rupture of the fetal membranes (FM), the amnion and choriodecidua, which normally surround and protect the fetus prior to delivery, is a major cause of preterm birth and results in significant infant mortality and morbidity. The physiological mechanism which normally leads the FM to weaken and fail prior to birth is not known. Conventional thinking that FM rupture is precipitated by the stress of uterine contractions during labor fails to explain the 10% of term deliveries and 40% of preterm deliveries in which FM rupture is the sentinel event, preceding any uterine contractions. Recent studies from several laboratories indicate that the FM undergo a genetically-programmed, biochemically-mediated, maturation process, near term, which is characterized by collagen remodeling and apoptosis. In human FM, in contrast to rat membranes, these changes are limited to the region of the FM overlying the cervix [1]. In a series of publications, our group has demonstrated that human FM have a zone of physical weakness (decreased force to rupture and work to rupture relative to the other areas of the same FM) overlying the cervical opening of the uterus. We further demonstrate that this same zone is characterized by specific markers of increased collagen remodeling and apoptosis [1–3]. These regional characteristics develop prior to the onset of contractions of labor and persist until delivery. Furthermore, the rupture tear line of the FM intersects this weak zone and thus the rupture process is hypothesized to initiate in this weak zone [3]. In order to investigate how differences in the biochemical composition of the extra-cellular matrix of the weak and the strong zones of FM reflect their different biomechanical properties, we utilized a proteomics approach to identify differences in the abundance of specific proteins in weak and strong FM fragments. Initial 2-DIGE screening resolved differences in Fibulin 5 protein expression. This prompted further analysis of additional members of the Fibulin protein family.

scholarly journals Proprioceptive feedback determines visuomotor gain inDrosophila

2015 ◽  
Author(s):  
Jan Bartussek ◽  
Fritz-Olaf Lehmann
Keyword(s):  
Temporal Structure ◽  
Physiological Mechanism ◽  
Sensory Information ◽  
Biomechanical Properties ◽  
Antagonistic Effect ◽  
Proprioceptive Feedback ◽  
Visual Object ◽  
Neural Activation ◽  
Precise Integration ◽  
Object Fixation

Multisensory integration is a prerequisite for effective locomotor control in most animals. Especially the impressive aerial performance of insects relies on rapid and precise integration of multiple sensory modalities that provide feedback on different time scales. In flies, continuous visual signalling from the compound eyes is fused with phasic proprioceptive feedback to ensure precise neural activation of wing steering muscles within narrow temporal phase bands of the stroke cycle. This phase-locked activation relies on mechanoreceptors distributed over wings and gyroscopic halteres. Here we investigate visual steering performance of tethered flying fruit flies with reduced haltere and wing feedback signalling. Using a flight simulator, we evaluated visual object fixation behaviour, optomotor altitude control, and saccadic escape reflexes. The behavioural assays show an antagonistic effect of wing and haltere signalling on visuomotor gain during flight. Compared to controls, suppression of haltere feedback attenuates while suppression of wing feedback enhances the animal's wing steering range. Our results suggest that the generation of motor commands owing to visual perception is dynamically controlled by proprioception. We outline a potential physiological mechanism based on the biomechanical properties of wing steering muscles and sensory integration processes at the level of motoneurons. Collectively, the findings contribute to our general understanding how moving animals integrate sensory information with dynamically changing temporal structure.

Synthesis of azabicycloalkanone amino acid and azapeptide mimics and their application as modulators of the prostaglandin F2α receptor for delaying preterm birth

2014 ◽  
Vol 92 (11) ◽  
pp. 1031-1040 ◽  
Author(s):  
Carine B. Bourguet ◽  
Audrey Claing ◽  
Stéphane A. Laporte ◽  
Terence E. Hébert ◽  
Sylvain Chemtob ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Amino Acid ◽  
Rational Design ◽  
Prostaglandin F2α ◽  
Receptor Activation ◽  
Therapeutic Agents ◽  
Biologically Active ◽  
Mortality And Morbidity ◽  
Amino Acid Peptide ◽  
Uterine Contractions

Premature birth (<37 weeks gestation) is the major cause of perinatal mortality and morbidity and has been steadily increasing worldwide. Towards the rational design of more effective therapeutic agents for inhibiting uterine contractions and prolonging gestation (a so-called tocolytic drug), our team has targeted the prostaglandin F2α receptor (FP) employing a peptidomimetic approach designed to provide modulators of this novel target. We identified first a lead peptide (PDC113) (1) based on the sequence of the second extracellular loop of FP on the basis that the loop itself might modulate receptor activation. Systematic study of the structure−activity relationships of 1 generated hypotheses concerning the conformation and side-chains responsible for activity that led to the synthesis of PDC113.31 (2), a potent all d-amino acid peptide, which has successfully completed Phase 1b clinical trials. Employing indolizidinone amino acids, peptide mimics were developed that served to probe the mechanism of FP modulation. For example, PDC113.824 (9) was shown to allosterically regulate FP activity contingent on the presence of prostaglandin F2α by a mechanism implicating biased signalling. Although attempts to understand the turn geometry responsible for the activity of 9 by replacement of its indolizidin-2-one moiety with other azabicycloalkanones failed to produce biologically active analogs, employment of aza-aminoacyl-proline analogs resulted in a series of FP modulators exhibiting distinct effects on different G protein-mediated signalling pathways. Our program has thus contributed novel probes for understanding the chemical biology of FP as well as new therapeutic agents with promise for inhibiting uterine contractions and preventing preterm birth.

scholarly journals AMP-Activated Protein (AMPK) in Pathophysiology of Pregnancy Complications

2018 ◽  
Vol 19 (10) ◽  
pp. 3076 ◽  
Author(s):  
Asako Kumagai ◽  
Atsuo Itakura ◽  
Daisuke Koya ◽  
Keizo Kanasaki
Keyword(s):  
Pregnancy Complications ◽  
Energy Homeostasis ◽  
Maternal Mortality Ratio ◽  
Careful Analysis ◽  
Whole Body ◽  
Fetal Membrane ◽  
Fetal Malformation ◽  
Mortality And Morbidity ◽  
Mortality Ratio ◽  
Body Energy

Although the global maternal mortality ratio has been consistently reduced over time, in 2015, there were still 303,000 maternal deaths throughout the world, of which 99% occurred in developing countries. Understanding pathophysiology of pregnancy complications contributes to the proper prenatal care for the reduction of prenatal, perinatal and neonatal mortality and morbidity ratio. In this review, we focus on AMP-activated protein kinase (AMPK) as a regulator of pregnancy complications. AMPK is a serine/threonine kinase that is conserved within eukaryotes. It regulates the cellular and whole-body energy homeostasis under stress condition. The functions of AMPK are diverse, and the dysregulation of AMPK is known to correlate with many disorders such as cardiovascular disease, diabetes, inflammatory disease, and cancer. During pregnancy, AMPK is necessary for the proper placental differentiation, nutrient transportation, maternal and fetal energy homeostasis, and protection of the fetal membrane. Activators of AMPK such as 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), resveratrol, and metformin restores pregnancy complications such as gestational diabetes mellitus (GDM), preeclampsia, intrauterine growth restriction, and preterm birth preclinically. We also discuss on the relationship between catechol-O-methyltransferase (COMT), an enzyme that metabolizes catechol, and AMPK during pregnancy. It is known that metformin cannot activate AMPK in COMT deficient mice, and that 2-methoxyestradiol (2-ME), a metabolite of COMT, recovers the AMPK activity, suggesting that COMT is a regulator of AMPK. These reports suggest the therapeutic use of AMPK activators for various pregnancy complications, however, careful analysis is required for the safe use of AMPK activators since AMPK activation could cause fetal malformation.

The Use of Mersilene Tape in Transabdominal Cerclage

2017 ◽  
Vol 752 ◽  
pp. 64-70
Author(s):  
Claudia Mehedințu ◽  
Ana Maria Rotaru ◽  
Marina Antonovici ◽  
Mihaela Plotogea ◽  
Elvira Brătilă ◽  
...  
Keyword(s):  
Biomechanical Properties ◽  
Uterine Wall ◽  
Medical Procedures ◽  
Genital Tract Infection ◽  
Uterine Contractions ◽  
Cervical Incompetence ◽  
Intrauterine Pressure ◽  
Uterine Growth ◽  
Mersilene Tape ◽  
Lower Genital Tract Infection

Aim: The purpose of this article is to show the use and utility of mersilene tape in medical procedures, such as transabdominal cerclage (TAC). Material and methods: Based on their biomechanical properties, we present our experience with mersilene tape used as treatment for cervical incompetence. Cervical insufficiency or cervical incompetence is defined as asymptomatic cervical shortening and dilatation with the absence of detectable uterine contractions. The mechanical properties of cervical tissue are derived from its extracellular matrix and its most important constituent the fibrillar collagen, alongside other constituents such as proteoglycans, hyaluronic acid, elastin, and water. In the absence of the uterine contractions, the cervix is loaded by intrauterine pressure (including the weight of the growing fetus and amniotic sac), the gravity as well as passive pressure from the uterine wall. These forces also depend on the support action of pelvic floor structures and abdominal wall. The static load resulting from the combination of uterine growth, hydrostatic pressure and gravity seems to be the dominant determinants that cause cervical shortening. The placement of the mersilene tape acts as a barrier between the intrauterine pressure and the cervix. The main advantage of the TAC procedure is the placement of the nonabsorbable suture (mersilene tape at the level of the internal os, avoiding the placement of a vaginal foreign body and subsequently increasing the risk of ascending lower genital tract infection, decreased incidence of slippage, and the ability to leave the stitch in place between pregnancies. Results: The follow-up was without complications regarding the pregnancies treated with transabdominal cerclage. None of the pregnancies terminated prematurely as related to the presence of the tape, but it necessitates to be performed a caesarean section for delivery. Conclusions: Mersilene tape is safe and useful in different medical procedures, including transabdominal cerclage during pregnancy.

Glycosaminoglycan and Collagen Remodeling During In Vitro Dynamic Compression of Articular Cartilage: Experiments and Finite Element Modeling

2013 ◽  
Author(s):  
Kevin A. Yamauchi ◽  
Christopher B. Raub ◽  
Albert C. Chen ◽  
Robert L. Sah ◽  
Scott J. Hazelwood ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Dynamic Compression ◽  
Fluid Velocity ◽  
Biomechanical Properties ◽  
Mechanical Stimuli ◽  
Unconfined Compression ◽  
Growth Data ◽  
Collagen Remodeling ◽  
Continuum Mixture Model

The biomechanical properties of articular cartilage (AC) can be altered by chemical and mechanical stimuli. Dynamic unconfined compression (UCC) has been shown to increase biosynthesis at moderate strain amplitudes (1–4%) and frequencies from 0.01Hz. to 0.1Hz [1]. Furthermore, interstitial fluid velocity and maximum principle strain have been proposed as candidates for controlling glycosaminoglycan (GAG) and collagen (COL) remodeling, respectively [2,3]. The goal of this study was to integrate in vitro growth data, including biochemical and microstructural properties, into a computational continuum mixture model to elucidate potential mechanical triggers for AC tissue remodeling.

scholarly journals Protein diversity in discrete structures at the distal tip of the trypanosome flagellum

2017 ◽  
Vol 114 (32) ◽  
pp. E6546-E6555 ◽  
Author(s):  
Vladimir Varga ◽  
Flavia Moreira-Leite ◽  
Neil Portman ◽  
Keith Gull
Keyword(s):  
Family Member ◽  
Biomechanical Properties ◽  
Protein Diversity ◽  
Functional Studies ◽  
Evolutionarily Conserved ◽  
Discrete Structures ◽  
Specific Proteins ◽  
Definition Of ◽  
Component Assembly

The distal end of the eukaryotic flagellum/cilium is important for axonemal growth and signaling and has distinct biomechanical properties. Specific flagellum tip structures exist, yet their composition, dynamics, and functions are largely unknown. We used biochemical approaches to identify seven constituents of the flagella connector at the tip of an assembling trypanosome flagellum and three constituents of the axonemal capping structure at the tips of both assembling and mature flagella. Both tip structures contain evolutionarily conserved as well as kinetoplastid-specific proteins, and component assembly into the structures occurs very early during flagellum extension. Localization and functional studies reveal that the flagella connector membrane junction is attached to the tips of extending microtubules of the assembling flagellum by a kinesin-15 family member. On the opposite side, a kinetoplastid-specific kinesin facilitates attachment of the junction to the microtubules in the mature flagellum. Functional studies also suggest roles of several other components and the definition of subdomains in the tip structures.

scholarly journals Proprioceptive feedback determines visuomotor gain in Drosophila

2016 ◽  
Vol 3 (1) ◽  
pp. 150562 ◽  
Author(s):  
Jan Bartussek ◽  
Fritz-Olaf Lehmann
Keyword(s):  
Temporal Structure ◽  
Physiological Mechanism ◽  
Sensory Information ◽  
Biomechanical Properties ◽  
Antagonistic Effect ◽  
Proprioceptive Feedback ◽  
Visual Object ◽  
Neural Activation ◽  
Precise Integration ◽  
Object Fixation

Multisensory integration is a prerequisite for effective locomotor control in most animals. Especially, the impressive aerial performance of insects relies on rapid and precise integration of multiple sensory modalities that provide feedback on different time scales. In flies, continuous visual signalling from the compound eyes is fused with phasic proprioceptive feedback to ensure precise neural activation of wing steering muscles (WSM) within narrow temporal phase bands of the stroke cycle. This phase-locked activation relies on mechanoreceptors distributed over wings and gyroscopic halteres. Here we investigate visual steering performance of tethered flying fruit flies with reduced haltere and wing feedback signalling. Using a flight simulator, we evaluated visual object fixation behaviour, optomotor altitude control and saccadic escape reflexes. The behavioural assays show an antagonistic effect of wing and haltere signalling on visuomotor gain during flight. Compared with controls, suppression of haltere feedback attenuates while suppression of wing feedback enhances the animal’s wing steering range. Our results suggest that the generation of motor commands owing to visual perception is dynamically controlled by proprioception. We outline a potential physiological mechanism based on the biomechanical properties of WSM and sensory integration processes at the level of motoneurons. Collectively, the findings contribute to our general understanding how moving animals integrate sensory information with dynamically changing temporal structure.

scholarly journals Matrisome Properties of Scaffolds Direct Fibroblasts in Idiopathic Pulmonary Fibrosis

2019 ◽  
Vol 20 (16) ◽  
pp. 4013 ◽  
Author(s):  
Linda Elowsson Rendin ◽  
Anna Löfdahl ◽  
Emma Åhrman ◽  
Catharina Müller ◽  
Thomas Notermans ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cellular Responses ◽  
Biomechanical Properties ◽  
Static Stretch ◽  
Cell Matrix ◽  
Associated Proteins ◽  
Approaches To Study ◽  
Specific Proteins ◽  
Cell Matrix Interactions

In idiopathic pulmonary fibrosis (IPF) structural properties of the extracellular matrix (ECM) are altered and influence cellular responses through cell-matrix interactions. Scaffolds (decellularized tissue) derived from subpleural healthy and IPF lungs were examined regarding biomechanical properties and ECM composition of proteins (the matrisome). Scaffolds were repopulated with healthy fibroblasts cultured under static stretch with heavy isotope amino acids (SILAC), to examine newly synthesized proteins over time. IPF scaffolds were characterized by increased tissue density, stiffness, ultimate force, and differential expressions of matrisome proteins compared to healthy scaffolds. Collagens, proteoglycans, and ECM glycoproteins were increased in IPF scaffolds, however while specific basement membrane (BM) proteins such as laminins and collagen IV were decreased, nidogen-2 was also increased. Findings were confirmed with histology, clearly showing a disorganized BM. Fibroblasts produced scaffold-specific proteins mimicking preexisting scaffold composition, where 11 out of 20 BM proteins were differentially expressed, along with increased periostin and proteoglycans production. We demonstrate how matrisome changes affect fibroblast activity using novel approaches to study temporal differences, where IPF scaffolds support a disorganized BM and upregulation of disease-associated proteins. These matrix-directed cellular responses emphasize the IPF matrisome and specifically the BM components as important factors for disease progression.

scholarly journals Development of ovine chorionic somatomammotropin hormone-deficient pregnancies

2016 ◽  
Vol 310 (9) ◽  
pp. R837-R846 ◽  
Author(s):  
Callie M. Baker ◽  
Lindsey N. Goetzmann ◽  
Jeremy D. Cantlon ◽  
Kimberly M. Jeckel ◽  
Quinton A. Winger ◽  
...  
Keyword(s):  
Intrauterine Growth Restriction ◽  
Fetal Liver ◽  
Secretory Product ◽  
Placental Development ◽  
Mortality And Morbidity ◽  
Chorionic Somatomammotropin ◽  
Near Term ◽  
High Concentrations ◽  
And Function

Intrauterine growth restriction (IUGR) is a leading cause of neonatal mortality and morbidity. Chorionic somatomammotropin hormone (CSH), a placenta-specific secretory product found at high concentrations in maternal and fetal circulation throughout gestation, is significantly reduced in human and sheep IUGR pregnancies. The objective of this study was to knock down ovine CSH ( oCSH) expression in vivo using lentiviral-mediated short-hairpin RNA to test the hypothesis that oCSH deficiency would result in IUGR of near-term fetal lambs. Three different lentiviral oCSH-targeting constructs were used and compared with pregnancies ( n = 8) generated with a scrambled control (SC) lentiviral construct. Pregnancies were harvested at 135 days of gestation. The most effective targeting sequence, “target 6” (tg6; n = 8), yielded pregnancies with significant reductions ( P ≤ 0.05) in oCSH mRNA (50%) and protein (38%) concentrations, as well as significant reductions ( P ≤ 0.05) in placental (52%) and fetal (32%) weights compared with the SC pregnancies. Fetal liver weights were reduced 41% ( P ≤ 0.05), yet fetal liver insulin-like growth factor-I ( oIGF1) and -II mRNA concentrations were reduced ( P ≤ 0.05) 82 and 71%, respectively, and umbilical artery oIGF1 concentrations were reduced 62% ( P ≤ 0.05) in tg6 pregnancies. Additionally, fetal liver oIGF-binding protein ( oIGFBP) 2 and oIGFBP3 mRNA concentrations were reduced ( P ≤ 0.05), whereas fetal liver oIGFBP1 mRNA concentration was not impacted nor was maternal liver o IGF and o IGFBP mRNA concentrations or uterine artery oIGF1 concentrations ( P ≥ 0.10). Based on our results, it appears that oCSH deficiency does result in IUGR, by impacting placental development as well as fetal liver development and function.

The Effect of Acupuncture on Uterine Contraction Induced by Oxytocin

2000 ◽  
Vol 28 (01) ◽  
pp. 35-40 ◽  
Author(s):  
Sok Cheon Pak ◽  
Chang Su Na ◽  
Jeong Sang Kim ◽  
Woo Suk Chae ◽  
Seiji Kamiya ◽  
...  
Keyword(s):  
Fetal Mortality ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Mortality And Morbidity ◽  
Uterine Contractions ◽  
Oxytocin Antagonists ◽  
Pressure Changes ◽  
Oxytocin Antagonist ◽  
Methods Of Treatment ◽  
Positive Results

Pretern labor (PTL) is one of the main causes of fetal mortality and morbidity in obstetrical medicine. Current methods of treatment are not very effective and often have significant side effects. For this reason new methods of preventing PTL are currently being sought. In Western medicine the newest development is oxytocin antagonists. In Oriental medicine acupuncture and moxibustion are being utilized for the purpose of stopping PTL. The goals of this study were to determine if acupuncture in pregnant rats can suppress oxytocin induced uterine contractions and to compare these results with those inhibited by an oxytocin antagonist. Uterine contractions were induced by continuous infusion of exogenous oxytocin. The first fetus in one uterine horn near the ovarian end was removed and distilled water-filled catheter was inserted into that vacated amniotic sac to measure uterine contractions as intrauterine pressure changes. Two acupoints of Ho-Ku (LI-4) and San-Yin-Chiao (Sp-6) were selected for acupuncture and Kuan-Yüan (Co-4) was used for moxibustion. The oxytocin-induced uterine contractions were significantly suppressed by acupuncture on the LI-4 (p < 0.05), but not by Sp-6. Stimulation of Co-4 by moxibustion had no significant (p > 0.05) tocolytic effect. The administration of oxytocin antagonist eliminated all the uterine contractions induced by oxytocin. The application of acupuncture to re-stimulate the activity that was suppressed by the oxytocin antagonist did not produce any positive results. However, prostaglandins did cause the uterus to contract. In conclusion, acupuncture on LI-4 was found to suppress uterine contractions induced by oxytocin in the pregnant rat. If acupuncture is similarly effective in counteracting the effects of oxytocin in women, then this may an alternative medical treatment for women in preterm labor.

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