scholarly journals The morphogenetic role of midline mesendoderm and ectoderm in the development of the forebrain and the midbrain of the mouse embryo

Development ◽  
2000 ◽  
Vol 127 (9) ◽  
pp. 1799-1813 ◽  
Author(s):  
A. Camus ◽  
B.P. Davidson ◽  
S. Billiards ◽  
P. Khoo ◽  
J.A. Rivera-Perez ◽  
...  
Keyword(s):  
Neural Tube ◽  
Mouse Embryo ◽  
De Novo ◽  
Gene Activity ◽  
Anteroposterior Patterning ◽  
De Novo Gene ◽  
Ventral Neural Tube ◽  
And Function ◽  
The Impact

The anterior midline tissue (AML) of the late gastrula mouse embryo comprises the axial mesendoderm and the ventral neuroectoderm of the prospective forebrain, midbrain and rostral hindbrain. In this study, we have investigated the morphogenetic role of defined segments of the AML by testing their inductive and patterning activity and by assessing the impact of their ablation on the patterning of the neural tube at the early-somite-stage. Both rostral and caudal segments of the AML were found to induce neural gene activity in the host tissue; however, the de novo gene activity did not show any regional characteristic that might be correlated with the segmental origin of the AML. Removal of the rostral AML that contains the prechordal plate resulted in a truncation of the head accompanied by the loss of several forebrain markers. However, the remaining tissues reconstituted Gsc and Shh activity and expressed the ventral forebrain marker Nkx2.1. Furthermore, analysis of Gsc-deficient embryos reveals that the morphogenetic function of the rostral AML requires Gsc activity. Removal of the caudal AML led to a complete loss of midline molecular markers anterior to the 4th somite. In addition, Nkx2.1 expression was not detected in the ventral neural tube. The maintenance and function of the rostral AML therefore require inductive signals emanating from the caudal AML. Our results point to a role for AML in the refinement of the anteroposterior patterning and morphogenesis of the brain.

scholarly journals Contribution of retrotransposition to developmental disorders

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Eugene J. Gardner ◽  
Elena Prigmore ◽  
Giuseppe Gallone ◽  
Petr Danecek ◽  
Kaitlin E. Samocha ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Purifying Selection ◽  
Selective Constraint ◽  
Protein Coding ◽  
Genome Wide ◽  
De Novo Gene ◽  
The Impact ◽  
Transcribed Sequences

Abstract Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

Myogenesis in paraxial mesoderm: preferential induction by dorsal neural tube and by cells expressing Wnt-1

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3675-3686 ◽  
Author(s):  
H.M. Stern ◽  
A.M. Brown ◽  
S.D. Hauschka
Keyword(s):  
Neural Tube ◽  
Muscle Development ◽  
Paraxial Mesoderm ◽  
Myogenic Response ◽  
Dorsal Neural Tube ◽  
Ventral Neural Tube ◽  
Myogenic Induction ◽  
Inductive Activity

Previous studies have demonstrated that the neural tube/notochord complex is required for skeletal muscle development within somites. In order to explore the localization of myogenic inducing signals within the neural tube, dorsal or ventral neural tube halves were cultured in contact with single somites or pieces of segmental plate mesoderm. Somites and segmental plates cultured with the dorsal half of the neural tube exhibited 70% and 85% myogenic response rates, as determined by immunostaining for myosin heavy chain. This response was slightly lower than the 100% response to whole neural tube/notochord, but was much greater than the 30% and 10% myogenic response to ventral neural tube with and without notochord. These results demonstrate that the dorsal neural tube emits a potent myogenic inducing signal which accounts for most of the inductive activity of whole neural tube/notochord. However, a role for ventral neural tube/notochord in somite myogenic induction was clearly evident from the larger number of myogenic cells induced when both dorsal neural tube and ventral neural tube/notochord were present. To address the role of a specific dorsal neural tube factor in somite myogenic induction, we tested the ability of Wnt-1-expressing fibroblasts to promote paraxial mesoderm myogenesis in vitro. We found that cells expressing Wnt-1 induced a small number of somite and segmental plate cells to undergo myogenesis. This finding is consistent with the localized dorsal neural tube inductive activity described above, but since the ventral neural tube/notochord also possesses myogenic inductive capacity yet does not express Wnt-1, additional inductive factors are likely involved.

scholarly journals Irritable bowel syndrome: new insights into symptom mechanisms and advances in treatment

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 780 ◽  
Author(s):  
Robin Spiller
Keyword(s):  
Irritable Bowel Syndrome ◽  
New Agents ◽  
Enteric Nerves ◽  
Inflammatory Bowel ◽  
Magnetic Resonance Imaging Mri ◽  
Irritable Bowel ◽  
Fodmap Diet ◽  
And Function ◽  
The Impact

Despite being one of the most common conditions leading to gastroenterological referral, irritable bowel syndrome (IBS) is poorly understood. However, recent years have seen major advances. These include new understanding of the role of both inflammation and altered microbiota as well as the impact of dietary intolerances as illuminated by magnetic resonance imaging (MRI), which has thrown new light on IBS. This article will review new data on how excessive bile acid secretion mediates diarrhea and evidence from post infectious IBS which has shown how gut inflammation can alter gut microbiota and function. Studies of patients with inflammatory bowel disease (IBD) have also shown that even when inflammation is in remission, the altered enteric nerves and abnormal microbiota can generate IBS-like symptoms. The efficacy of the low FODMAP diet as a treatment for bloating, flatulence, and abdominal discomfort has been demonstrated by randomized controlled trials. MRI studies, which can quantify intestinal volumes, have provided new insights into how FODMAPs cause symptoms. This article will focus on these areas together with recent trials of new agents, which this author believes will alter clinical practice within the foreseeable future.

scholarly journals Peran Pendidikan Etika Kristen dalam Media Sosial di Era Disrupsi

2020 ◽  
Vol 1 (1) ◽  
pp. 38-46
Author(s):  
Mesirawati Waruwu ◽  
Yonatan Alex Arifianto ◽  
Aji Suseno
Keyword(s):  
Social Media ◽  
Ethics Education ◽  
Christian Ethics ◽  
Christian Faith ◽  
Ethical Challenges ◽  
Use Of Social Media ◽  
And Function ◽  
Meaning And Function ◽  
The Impact

The limitless development of social media, its meaning and function have begun to shift, no longer as a means of establishing relationships, communication, but at the stage of losing the role of ethics and morals, even disputes have occurred triggered by debates from communicating in social media. The purpose of this study is to describe the role of Christian ethics education in relation to the impact of social media development in the era of disruption. Using descriptive qualitative methods with literature literature can find solutions for believers in facing moral decadence due to social media abuse by knowing the era of disruption and ethical challenges from the wrong use of social media can affect moral decadence so that Christian ethics education on a biblical basis can bring modern humans. Believers in particular have become bright in social media and their use in accordance with Christian faith in this era of disruption.

P–182 The mechanism of mouse embryo hatching and the impact of laser drilling the zona pellucida: an RNA sequencing study

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Y Liu ◽  
C Jones ◽  
K Coward
Keyword(s):  
Treatment Group ◽  
Mouse Embryo ◽  
Mouse Embryos ◽  
Z Score ◽  
Rna Seq ◽  
Metabolism Pathway ◽  
Hatching Process ◽  
The Impact

Abstract Study question What is the mechanism of embryo hatching? Will laser-assisted zona pellucida (ZP) drilling alter the embryonic transcriptome? Summary answer Hatching is an ATP-dependent process. Hatching is also associated with Rho-mediated signaling. Laser-assisted ZP drilling might cause alternation in embryo metabolism. What is known already Embryo hatching is a vital process for early embryo development and implantation. Animal data suggests that hatching is the result of multiple factors, such as mechanical pressure, protease activation, and the regulation of maternal secretions. However, little is known about the regulatory signaling mechanisms and the molecules involved. In addition, despite the extensive use of laser-assisted ZP drilling in the clinic, the safety profile of this technique at molecular level is very sparse. The impact of this technique on the embryonic transcriptome has not been studied systematically. Study design, size, duration Eighty mouse embryos were randomly divided into a laser ZP drilling group (n = 40) and an untreated group (n = 40). After treatment, embryos were cultured in vitro for two days. Then, hatching blastocyst (n = 8) and pre-hatching blastocyst (n = 8) from the untreated group, and the hatching blastocyst from the treatment group (n = 8) were processed for RNA sequencing (RNA-seq). Participants/materials, setting, methods Cryopreserved 8-cell stage mouse embryos (B6C3F1 × B6D2F1) were thawed, and a laser was used to drill the embryo ZP in the treatment group. Next, the treated and untreated embryos were individually cultured in vitro to the E4.5 blastocyst stage. The resulting blastocysts were lysed individually and used for subsequent cDNA library preparation and RNA-seq. Following data quality control and alignment, the RNA-seq data were processed for differentially expressed gene analysis and downstream functional analysis. Main results and the role of chance According to the RNA-seq data, 275 differentially expressed genes (DEGs) (230 up-regulated and 45 down-regulated, adjusted P < 0.05) were identified when comparing hatching and pre-hatching blastocysts in the control groups. Analysis suggested that the trophectoderm is the primary cell type involved in hatching, and revealed the potential molecules causing increased blastocyst hydrostatic pressure (Aqp3 and Cldn4). Functional enrichment analysis suggested that ATP metabolism and protein synthesis were activated in hatching blastocysts. DEGs were found to be significantly enriched in several gene ontology terms, particularly in terms of the organization of the cytoskeleton and actin polymerisation (P < 0.0001). Furthermore, according to QIAGEN ingenuity pathway analysis results, Rho signaling was implicated in blastocyst hatching (Actb, Arpc2, Cfl1, Myl6, Pfn1, Rnd3, Septin9, z-score=2.65, P < 0.0001). Moreover, the potential role of hormones (estrogen (z-score=2.24) and prolactin (z-score=2.4)) and growth factors (AGT (z-score=2.41) and FGF2 (z-score=2.213)) were implicated in the hatching process as indicated by the upstream regulator analysis. By comparing the transcriptome between laser-treated and untreated hatching blastocysts, 47 DEGs were identified (adjusted P < 0.05) following laser-assisted ZP drilling. These genes were enriched in metabolism-related pathways (P < 0.05), including the lipid metabolism pathway (Mvd, Mvk, Aacs, Gsk3a, Pik3c2a, Aldh9a1) and the xenobiotic metabolism pathway (Aldh18a1, Aldh9a1, Keap1, and Pik3c2a). Limitations, reasons for caution Findings in mouse embryos may not be fully representative of human embryos. Furthermore, the mechanism of hatching revealed here might only reflect the hatching process of embryos in vitro. Further studies are now necessary to confirm these findings in different conditions and species to determine their clinical significance. Wider implications of the findings: Our study profiled the mouse embryo transcriptome during in vitro hatching, identified potential key genes and mechanisms for future study. In addition, for the first time, we revealed the impact of laser-assisted ZP drilling on the transcriptome, this may help us to assess and improve the existing technique. Trial registration number Not applicable

scholarly journals Contribution of HIV Infection, AIDS, and Antiretroviral Therapy to Exocrine Pathogenesis in Salivary and Lacrimal Glands

2018 ◽  
Vol 19 (9) ◽  
pp. 2747 ◽  
Author(s):  
Imran Nizamuddin ◽  
Peter Koulen ◽  
Carole McArthur
Keyword(s):  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Exocrine Function ◽  
Lacrimal Glands ◽  
Immunodeficiency Virus ◽  
And Function ◽  
The Impact

The structure and function of exocrine glands are negatively affected by human immunodeficiency virus (HIV) infection and its co-morbidities, including innate and adaptive immune responses. At the same time, exocrine function may also be influenced by pharmacotherapies directed at the infectious agents. Here, we briefly review the role of the salivary glands and lacrimal glands in normal physiology and exocrine pathogenesis within the context of HIV infection and acquired immune deficiency syndrome (AIDS), including the contribution of antiretroviral therapies on both. Subsequently, we discuss the impact of HIV infection and the types of antiretroviral therapy on disease management and therapy development efforts.

Platelet microparticles reprogram macrophage gene expression and function

2016 ◽  
Vol 115 (02) ◽  
pp. 311-323 ◽  
Author(s):  
Matthieu Rousseau ◽  
Anne-Claire Duchez ◽  
Chan Ho C. Lee ◽  
Eric Boilard ◽  
Benoit Laffont ◽  
...  
Keyword(s):  
Actinomycin D ◽  
De Novo ◽  
Phagocytic Capacity ◽  
Human Macrophages ◽  
Mrna Targets ◽  
De Novo Gene ◽  
Supplementary Material ◽  
And Function ◽  
Microarray Analyses ◽  
Platelet Microparticles

SummaryPlatelet microparticles (MPs) represent the most abundant MPs subtype in the circulation, and can mediate intercellular communication through delivery of bioactives molecules, such as cytokines, proteins, lipids and RNAs. Here, we show that platelet MPs can be internalised by primary human macrophages and deliver functional miR-126–3p. The increase in macrophage miR-126–3p levels was not prevented by actinomycin D, suggesting that it was not due to de novo gene transcription. Platelet MPs dose-dependently downregulated expression of four predicted mRNA targets of miR-126–3p, two of which were confirmed also at the protein level. The mRNA downregulatory effects of platelet MPs were abrogated by expression of a neutralising miR-126–3p sponge, implying the involvement of miR-126–3p. Transcriptome-wide, microarray analyses revealed that as many as 66 microRNAs and 653 additional RNAs were significantly and differentially expressed in macrophages upon exposure to platelet MPs. More specifically, platelet MPs induced an upregulation of 34 microRNAs and a concomitant downregulation of 367 RNAs, including mRNAs encoding for cytokines/chemokines CCL4, CSF1 and TNF. These changes were associated with reduced CCL4, CSF1 and TNF cytokine/chemokine release by macrophages, and accompanied by a marked increase in their phagocytic capacity. These findings demonstrate that platelet MPs can modify the transcriptome of macrophages, and reprogram their function towards a phagocytic phenotype.Supplementary Material to this article is available online at www.thrombosis-online.com.

A stochastic roadmap method to model protein structural transitions

Robotica ◽  
2015 ◽  
Vol 34 (8) ◽  
pp. 1705-1733 ◽  
Author(s):  
Kevin Molloy ◽  
Rudy Clausen ◽  
Amarda Shehu
Keyword(s):  
Protein Structure ◽  
Molecular Basis ◽  
Structure And Function ◽  
Structural Transitions ◽  
Simulation Framework ◽  
Human Disorders ◽  
Model Protein ◽  
And Function ◽  
The Impact

SUMMARYEvidence is emerging that the role of protein structure in disease needs to be rethought. Sequence mutations in proteins are often found to affect the rate at which a protein switches between structures. Modeling structural transitions in wildtype and variant proteins is central to understanding the molecular basis of disease. This paper investigates an efficient algorithmic realization of the stochastic roadmap simulation framework to model structural transitions in wildtype and variants of proteins implicated in human disorders. Our results indicate that the algorithm is able to extract useful information on the impact of mutations on protein structure and function.

scholarly journals The conformational and mutational landscape of the ubiquitin-like marker for the autophagosome formation in cancer

2019 ◽  
Author(s):  
Burcu Aykac Fas ◽  
Mukesh Kumar ◽  
Valentina Sora ◽  
Maliha Mashkoor ◽  
Matteo Lambrughi ◽  
...  
Keyword(s):  
Physical Models ◽  
Missense Mutations ◽  
Cancer Types ◽  
Neutral Mutations ◽  
And Function ◽  
Cellular Components ◽  
The Impact ◽  
Pan Cancer ◽  
Structural Ensemble

AbstractAutophagy is a cellular process to recycle damaged cellular components and its modulation can be exploited for disease treatments. A key autophagy player is a ubiquitin-like protein, LC3B. Compelling evidence attests the role of autophagy and LC3B in different cancer types. Many LC3B structures have been solved, but a comprehensive study, including dynamics, has not been yet undertaken. To address this knowledge gap, we assessed ten physical models for molecular dynamics for their capabilities to describe the structural ensemble of LC3B in solution using different metrics and comparison with NMR data. With the resulting LC3B ensembles, we characterized the impact of 26 missense mutations from Pan-Cancer studies with different approaches. Our findings shed light on driver or neutral mutations in LC3B, providing an atlas of its modifications in cancer. Our framework could be used to assess the pathogenicity of mutations by accounting for the different aspects of protein structure and function altered by mutational events.

scholarly journals Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2314
Author(s):  
Lisa Kurmann ◽  
Michal Okoniewski ◽  
Raghvendra K. Dubey
Keyword(s):  
Endothelial Cells ◽  
Cell Migration ◽  
Human Brain ◽  
Neurovascular Unit ◽  
Active Role ◽  
Migration Activity ◽  
Akt Phosphorylation ◽  
And Function ◽  
The Impact

Stroke is the third leading cause of mortality in women and it kills twice as many women as breast cancer. A key role in the pathophysiology of stroke plays the disruption of the blood–brain barrier (BBB) within the neurovascular unit. While estrogen induces vascular protective actions, its influence on stroke remains unclear. Moreover, experiments assessing its impact on endothelial cells to induce barrier integrity are non-conclusive. Since pericytes play an active role in regulating BBB integrity and function, we hypothesize that estradiol may influence BBB by regulating their activity. In this study using human brain vascular pericytes (HBVPs) we investigated the impact of estradiol on key pericyte functions known to influence BBB integrity. HBVPs expressed estrogen receptors (ER-α, ER-β and GPER) and treatment with estradiol (10 nM) inhibited basal cell migration but not proliferation. Since pericyte migration is a hallmark for BBB disruption following injury, infection and inflammation, we investigated the effects of estradiol on TNFα-induced PC migration. Importantly, estradiol prevented TNFα-induced pericyte migration and this effect was mimicked by PPT (ER-α agonist) and DPN (ER-β agonist), but not by G1 (GPR30 agonist). The modulatory effects of estradiol were abrogated by MPP and PHTPP, selective ER-α and ER-β antagonists, respectively, confirming the role of ER-α and ER-β in mediating the anti-migratory actions of estrogen. To delineate the intracellular mechanisms mediating the inhibitory actions of estradiol on PC migration, we investigated the role of AKT and MAPK activation. While estradiol consistently reduced the TNFα-induced MAPK and Akt phosphorylation, only the inhibition of MAPK, but not Akt, significantly abrogated the migratory actions of TNFα. In transendothelial electrical resistance measurements, estradiol induced barrier function (TEER) in human brain microvascular endothelial cells co-cultured with pericytes, but not in HBMECs cultured alone. Importantly, transcriptomics analysis of genes modulated by estradiol in pericytes showed downregulation of genes known to increase cell migration and upregulation of genes known to inhibit cell migration. Taken together, our findings provide the first evidence that estradiol modulates pericyte activity and thereby improves endothelial integrity.

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