scholarly journals Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Biallelic Loss of ENG or ACVRL1

2019 ◽  
Author(s):  
Daniel Snellings ◽  
Carol Gallione ◽  
Dewi Clark ◽  
Nicholas Vozoris ◽  
Marie Faughnan ◽  
...  
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Somatic Mutations ◽  
Vascular Malformations ◽  
Low Frequency ◽  
The Body ◽  
Mendelian Disease ◽  
Loss Of Function ◽  
Long Read ◽  
In Trans ◽  
Vascular Defect

AbstractHereditary Hemorrhagic Telangiectasia (HHT) is a Mendelian disease characterized by vascular malformations including visceral arteriovenous malformations and mucosal telangiectasia. HHT is caused by loss-of-function mutations in one of 3 genes; ENG, ACVRL1 or SMAD4 and is inherited as an autosomal dominant condition. Intriguingly, the constitutional mutation causing HHT is present throughout the body, yet the multiple vascular malformations in HHT patients occur focally, rather than manifesting as a systemic vascular defect. This disconnect between genotype and phenotype suggests that a local event is necessary for the development of vascular malformations. We investigated the hypothesis that local somatic mutations seed the formation HHT-related telangiectasia in a genetic two-hit mechanism. We identified low-frequency somatic mutations in 9/19 telangiectasia using high depth next-generation sequencing. We established phase for 7 of 9 samples using long-read sequencing, which confirm that the germline and somatic mutations in all 7 samples exist in trans configuration; consistent with a genetic two-hit mechanism. These combined data suggest that biallelic loss of ENG or ACVRL1 may be a required event in the development of telangiectasia, and that rather than haploinsufficiency, vascular malformations in HHT are caused by a Knudsonian two-hit mechanism.

scholarly journals Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1

2019 ◽  
Vol 105 (5) ◽  
pp. 894-906 ◽  
Author(s):  
Daniel A. Snellings ◽  
Carol J. Gallione ◽  
Dewi S. Clark ◽  
Nicholas T. Vozoris ◽  
Marie E. Faughnan ◽  
...  
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Somatic Mutations ◽  
Vascular Malformations ◽  
Allelic Loss

scholarly journals Slithering CSF: Cerebrospinal Fluid Dynamics in the Stationary and Moving Viper Boa, Candoia aspera

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 672
Author(s):  
Bruce A. Young ◽  
Skye Greer ◽  
Michael Cramberg
Keyword(s):  
Cerebrospinal Fluid ◽  
Cardiac Cycle ◽  
Low Frequency ◽  
Mean Amplitude ◽  
The Body ◽  
Body Waves ◽  
Lower Amplitude ◽  
Lateral Undulation ◽  
Recovery From Anesthesia ◽  
The Relationship

In the viper boa (Candoia aspera), the cerebrospinal fluid (CSF) shows two stable overlapping patterns of pulsations: low-frequency (0.08 Hz) pulses with a mean amplitude of 4.1 mmHg that correspond to the ventilatory cycle, and higher-frequency (0.66 Hz) pulses with a mean amplitude of 1.2 mmHg that correspond to the cardiac cycle. Manual oscillations of anesthetized C. aspera induced propagating sinusoidal body waves. These waves resulted in a different pattern of CSF pulsations with frequencies corresponding to the displacement frequency of the body and with amplitudes greater than those of the cardiac or ventilatory cycles. After recovery from anesthesia, the snakes moved independently using lateral undulation and concertina locomotion. The episodes of lateral undulation produced similar influences on the CSF pressure as were observed during the manual oscillations, though the induced CSF pulsations were of lower amplitude during lateral undulation. No impact on the CSF was found while C. aspera was performing concertina locomotion. The relationship between the propagation of the body and the CSF pulsations suggests that the body movements produce an impulse on the spinal CSF.

scholarly journals Vascular endothelial cell specification in health and disease

Angiogenesis ◽  
2021 ◽  
Author(s):  
Corina Marziano ◽  
Gael Genet ◽  
Karen K. Hirschi
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Current Knowledge ◽  
Vascular Malformations ◽  
Immune Surveillance ◽  
Vascular Endothelial Cell ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cell ◽  
The Body ◽  
Vascular Networks

AbstractThere are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.

scholarly journals Identification and Characterization of Genes That Interact With lin-12 in Caenorhabditis elegans

Genetics ◽  
1997 ◽  
Vol 147 (4) ◽  
pp. 1675-1695 ◽  
Author(s):  
Frans E Tax ◽  
James H Thomas ◽  
Edwin L Ferguson ◽  
H Robert Horvitzt
Keyword(s):  
Cell Fate ◽  
Low Frequency ◽  
Signal Transduction Pathway ◽  
Temperature Shift ◽  
Egg Laying ◽  
Null Alleles ◽  
Temperature Sensitive ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Suppressor Mutations

Abstract We identified and characterized 14 extragenic mutations that suppressed the dominant egg-laying defect of certain lin-12 gain-of-function mutations. These suppressors defined seven genes: sup-l7, lag-2, sel-4, sel-5, sel-6, sel-7 and sel-8. Mutations in six of the genes are recessive suppressors, whereas the two mutations that define the seventh gene, lag-2, are semi-dominant suppressors. These suppressor mutations were able to suppress other lin-12 gain-of-function mutations. The suppressor mutations arose at a very low frequency per gene, 10-50 times below the typical loss-of-function mutation frequency. The suppressor mutations in sup1 7 and lag-2 were shown to be rare non-null alleles, and we present evidence that null mutations in these two genes cause lethality. Temperature-shift studies for two suppressor genes, sup1 7and lag-2, suggest that both genes act at approximately the same time as lin-12in specifying a cell fate. Suppressor alleles of six of these genes enhanced a temperature-sensitive loss-of-function allele of glp-1, a gene related to lin-12 in structure and function. Our analysis of these suppressors suggests that the majority of these genes are part of a shared lin-12/glp-1 signal transduction pathway, or act to regulate the expression or stability of lin-12 and glp-1.

scholarly journals Predictors of mortality in patients with hereditary hemorrhagic telangiectasia

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
K. P. Thompson ◽  
◽  
J. Nelson ◽  
H. Kim ◽  
L. Pawlikowska ◽  
...  
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Cox Regression ◽  
Clinical Symptoms ◽  
Vascular Malformations ◽  
Smoking Status ◽  
Treatment Options ◽  
Gi Bleeding ◽  
Cox Regression Analysis ◽  
Predictors Of Mortality

Abstract Background Retrospective questionnaire and healthcare administrative data suggest reduced life expectancy in untreated hereditary hemorrhagic telangiectasia (HHT). Prospective data suggests similar mortality, to the general population, in Denmark’s centre-treated HHT patients. However, clinical phenotypes vary widely in HHT, likely affecting mortality. We aimed to measure predictors of mortality among centre-treated HHT patients. HHT patients were recruited at 14 HHT centres of the Brain Vascular Malformation Consortium (BVMC) since 2010 and followed annually. Vital status, organ vascular malformations (VMs) and clinical symptoms data were collected at baseline and during follow-up (N = 1286). We tested whether organ VMs, HHT symptoms and HHT genes were associated with increased mortality using Cox regression analysis, adjusting for patient age, sex, and smoking status. Results 59 deaths occurred over average follow-up time of 3.4 years (max 8.6 years). A history of anemia was associated with increased mortality (HR = 2.93, 95% CI 1.37–6.26, p = 0.006), as were gastro-intestinal (GI) bleeding (HR = 2.63, 95% CI 1.46–4.74, p = 0.001), and symptomatic liver VMs (HR = 2.10, 95% CI 1.15–3.84, p = 0.015). Brain VMs and pulmonary arteriovenous malformations (AVMs) were not associated with mortality (p > 0.05). Patients with SMAD4 mutation had significantly higher mortality (HR = 18.36, 95% CI 5.60–60.20, p < 0.001) compared to patients with ACVRL1 or ENG mutation, but this estimate is imprecise given the rarity of SMAD4 patients (n = 33, 4 deaths). Conclusions Chronic GI bleeding, anemia and symptomatic liver VMs are associated with increased mortality in HHT patients, independent of age, and in keeping with the limited treatment options for these aspects of HHT. Conversely, mortality does not appear to be associated with pulmonary AVMs or brain VMs, for which patients are routinely screened and treated preventatively at HHT Centres. This demonstrates the need for development of new therapies to treat chronic anemia, GI bleeding, and symptomatic liver VMs in order to reduce mortality among HHT patients.

scholarly journals Amynthas corticis genome reveals molecular mechanisms behind global distribution

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Xing Wang ◽  
Yi Zhang ◽  
Yufeng Zhang ◽  
Mingming Kang ◽  
Yuanbo Li ◽  
...  
Keyword(s):  
Genome Assembly ◽  
Molecular Mechanisms ◽  
Gene Families ◽  
The Body ◽  
Gene Family Evolution ◽  
Complex Environments ◽  
Protein Coding ◽  
Itraq Analysis ◽  
Rdna Sequencing ◽  
Long Read

AbstractEarthworms (Annelida: Crassiclitellata) are widely distributed around the world due to their ancient origination as well as adaptation and invasion after introduction into new habitats over the past few centuries. Herein, we report a 1.2 Gb complete genome assembly of the earthworm Amynthas corticis based on a strategy combining third-generation long-read sequencing and Hi-C mapping. A total of 29,256 protein-coding genes are annotated in this genome. Analysis of resequencing data indicates that this earthworm is a triploid species. Furthermore, gene family evolution analysis shows that comprehensive expansion of gene families in the Amynthas corticis genome has produced more defensive functions compared with other species in Annelida. Quantitative proteomic iTRAQ analysis shows that expression of 147 proteins changed in the body of Amynthas corticis and 16 S rDNA sequencing shows that abundance of 28 microorganisms changed in the gut of Amynthas corticis when the earthworm was incubated with pathogenic Escherichia coli O157:H7. Our genome assembly provides abundant and valuable resources for the earthworm research community, serving as a first step toward uncovering the mysteries of this species, and may provide molecular level indicators of its powerful defensive functions, adaptation to complex environments and invasion ability.

A Parametric Study of Low-Frequency Damping of Mooring System

2014 ◽  
Author(s):  
Minglu Chen ◽  
Shan Huang ◽  
Nigel Baltrop ◽  
Ji Chunyan ◽  
Liangbi Li
Keyword(s):  
Low Frequency ◽  
Structure Design ◽  
The Body ◽  
Body Motion ◽  
Mooring Line ◽  
Offshore Structure ◽  
Frequency Oscillation ◽  
Low Frequency Oscillation ◽  
Line System ◽  
Irregular Wave

Mooring line damping plays an important role to the body motion of moored floating platforms. Meanwhile, it can also make contributions to optimize the mooring line system. Accurate assessment of mooring line damping is thus an essential issue for offshore structure design. However, it is difficult to determine the mooring line damping based on theoretical methods. This study considers the parameters which have impact on mooring-induced damping. In the paper, applying Morison formula to calculate the drag and initial force on the mooring line, its dynamic response is computed in the time domain. The energy dissipation of the mooring line due to the viscosity was used to calculate mooring-induced damping. A mooring line is performed with low-frequency oscillation only, the low-frequency oscillation superimposed with regular and irregular wave-frequency motions. In addition, the influences of current velocity, mooring line pretension and different water depths are taken into account.

scholarly journals Mutation spectrum of NOD2 reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Julie E. Horowitz ◽  
Neil Warner ◽  
Jeffrey Staples ◽  
Eileen Crowley ◽  
Nehal Gosalia ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Protein Function ◽  
Early Onset ◽  
Low Frequency ◽  
Mendelian Inheritance ◽  
Clinical Population ◽  
Mendelian Disease ◽  
Recessive Inheritance ◽  
Pediatric Onset

AbstractInflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥ 25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments. NOD2 was the first and is the most replicated locus associated with adult IBD, to date. However, its role in pediatric onset IBD is not well understood. We performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0–18.5 years). We identified 92 probands with biallelic rare and low frequency NOD2 variants accounting for approximately 8% of our cohort, suggesting a Mendelian inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance of NOD2 alleles in adult IBD patients from a large clinical population cohort. We found that recessive inheritance of NOD2 variants explains ~ 7% of cases in this adult IBD cohort, including ~ 10% of CD cases, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that several of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. While it has been previously reported that carriers of more than one NOD2 risk alleles have increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate that recessive inheritance of NOD2 alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Collectively, our findings show that recessive inheritance of rare and low frequency deleterious NOD2 variants account for 7–10% of CD cases and implicate NOD2 as a Mendelian disease gene for early onset Crohn’s Disease.

Médiation phénoménale du corps vécu. Embodiment et corporéalité en émergence sous l’effet des technologies

2020 ◽  
Vol 22 ◽  
pp. 333-349
Author(s):  
Isabelle Choinière ◽  
Keyword(s):  
The Body ◽  
Lived Body ◽  
Changing Environment ◽  
Transdisciplinary Approach ◽  
Technological Environment ◽  
Physical Body ◽  
In Trans

The mediation of the performative body raises the question of the re-evaluation of the lived body in relation to phenomena of re-creation or re-composition involving the sensible and somatic body when it is affected by technology and incorporates its effects. To understand this phenomenon, this essay examines the interrelation of the notions of corporality (a notion which concerns the physical body in its materiality, or the anthropomorphic body), corporeality, and embodiment through a transdisciplinary approach and as an anchoring to a dynamic of self-eco-organization. Merleau-Ponty’s philosophy underpins the very foundations of this research and will allow us to reflect on the new status of the contemporary body in technological contexts. Two main notions will be used. “Corporeality”, as a form of the lived body and a transdisciplinary concept and embodiment as an act of integration by the body – here in a technological environment. In the evolution of the interrelation between the body and the changing environment, the two are in trans-relation, a trans-formation occurs. To conclude, we propose to analyze these new “realities” in a Merleau-Pontian and Nietzschean interconnected approach, that is, through a philosophy of becoming, a philosophy that flows through the body: being a body, doing, risking and creating – a philosophy that resonates with this trans-formation.

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