scholarly journals Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities

2021 ◽  
Vol 22 (11) ◽  
pp. 6167
Author(s):  
Carla Liaci ◽  
Mattia Camera ◽  
Giovanni Caslini ◽  
Simona Rando ◽  
Salvatore Contino ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Systems Biology ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Pathological Condition ◽  
Hierarchical Arrangement ◽  
Worldwide Population ◽  
Id Genes ◽  
Effective Network ◽  
And Behavior

Intellectual disability (ID) is a pathological condition characterized by limited intellectual functioning and adaptive behaviors. It affects 1–3% of the worldwide population, and no pharmacological therapies are currently available. More than 1000 genes have been found mutated in ID patients pointing out that, despite the common phenotype, the genetic bases are highly heterogeneous and apparently unrelated. Bibliomic analysis reveals that ID genes converge onto a few biological modules, including cytoskeleton dynamics, whose regulation depends on Rho GTPases transduction. Genetic variants exert their effects at different levels in a hierarchical arrangement, starting from the molecular level and moving toward higher levels of organization, i.e., cell compartment and functions, circuits, cognition, and behavior. Thus, cytoskeleton alterations that have an impact on cell processes such as neuronal migration, neuritogenesis, and synaptic plasticity rebound on the overall establishment of an effective network and consequently on the cognitive phenotype. Systems biology (SB) approaches are more focused on the overall interconnected network rather than on individual genes, thus encouraging the design of therapies that aim to correct common dysregulated biological processes. This review summarizes current knowledge about cytoskeleton control in neurons and its relevance for the ID pathogenesis, exploiting in silico modeling and translating the implications of those findings into biomedical research.

Alzheimer’s Disease and Retinal Degeneration: A Glimpse at Essential Trace Metals in Ocular Fluids and Tissues

2020 ◽  
Vol 16 (12) ◽  
pp. 1073-1083 ◽  
Author(s):  
Alessandra Micera ◽  
Luca Bruno ◽  
Andrea Cacciamani ◽  
Mauro Rongioletti ◽  
Rosanna Squitti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Trace Metals ◽  
Late Onset ◽  
Current Knowledge ◽  
Pathological Condition ◽  
Retinal Disease ◽  
Cellular Aging ◽  
Research Strategies ◽  
Aged People

Background: Life expectancy is increasing all over the world, although neurodegenerative disorders might drastically affect the individual activity of aged people. Of those, Alzheimer’s Disease (AD) is one of the most social-cost age-linked diseases of industrialized countries. To date, retinal diseases seem to be more common in the developing world and characterize principally aged people. Agerelated Macular Degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with AD, including stress stimuli such as oxidative stress, inflammation and amyloid formations. Method: In both diseases, the detrimental intra/extra-cellular deposits have many similarities. Aging, hypercholesterolemia, hypertension, obesity, arteriosclerosis and smoking are risk factors to develop both diseases. Cellular aging routes have similar organelle and signaling patterns in retina and brain. The possibility to find out new research strategies represent a step forward to disclose potential treatment for both of them. Essential trace metals play critical roles in both physiological and pathological condition of retina, optic nerve and brain, by influencing metabolic processes chiefly upon complex multifactorial pathogenesis. Conclusion: Hence, this review addresses current knowledge about some up-to-date investigated essential trace metals associated with AD and AMD. Changes in the levels of systemic and ocular fluid essential metals might reflect the early stages of AMD, possibly disclosing neurodegeneration pathways shared with AD, which might open to potential early detection.

scholarly journals The Multiple Functions of Rho GTPases in Fission Yeasts

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1422
Author(s):  
Jero Vicente-Soler ◽  
Teresa Soto ◽  
Alejandro Franco ◽  
José Cansado ◽  
Marisa Madrid
Keyword(s):  
Fission Yeast ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Model Organism ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Physiological Processes ◽  
Evolutionary Changes ◽  
Rho Family

The Rho family of GTPases represents highly conserved molecular switches involved in a plethora of physiological processes. Fission yeast Schizosaccharomyces pombe has become a fundamental model organism to study the functions of Rho GTPases over the past few decades. In recent years, another fission yeast species, Schizosaccharomyces japonicus, has come into focus offering insight into evolutionary changes within the genus. Both fission yeasts contain only six Rho-type GTPases that are spatiotemporally controlled by multiple guanine–nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and whose intricate regulation in response to external cues is starting to be uncovered. In the present review, we will outline and discuss the current knowledge and recent advances on how the fission yeasts Rho family GTPases regulate essential physiological processes such as morphogenesis and polarity, cellular integrity, cytokinesis and cellular differentiation.

scholarly journals Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 66
Author(s):  
Rashmita Pradhan ◽  
Phuong A. Ngo ◽  
Luz d. C. Martínez-Sánchez ◽  
Markus F. Neurath ◽  
Rocío López-Posadas
Keyword(s):  
Intestinal Mucosa ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Cell Types ◽  
Effector Proteins ◽  
Special Focus ◽  
Specific Cell ◽  
Rho Proteins

Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and the interaction with downstream effector proteins in close proximity to the membrane. A plethora of in vitro studies demonstrate the indispensable function of Rho proteins for cytoskeleton dynamics within different cell types. However, only in the last decades we have got access to genetically modified mouse models to decipher the intricate regulation between members of the Rho family within specific cell types in the complex in vivo situation. Translationally, alterations of the expression and/or function of Rho GTPases have been associated with several pathological conditions, such as inflammation and cancer. In the context of the GI tract, the continuous crosstalk between the host and the intestinal microbiota requires a tight regulation of the complex interaction between cellular components within the intestinal tissue. Recent studies demonstrate that Rho GTPases play important roles for the maintenance of tissue homeostasis in the gut. We will summarize the current knowledge on Rho protein function within individual cell types in the intestinal mucosa in vivo, with special focus on intestinal epithelial cells and T cells.

scholarly journals Activated Rho GTPases in Cancer—The Beginning of a New Paradigm

2018 ◽  
Vol 19 (12) ◽  
pp. 3949 ◽  
Author(s):  
Pontus Aspenström
Keyword(s):  
Cancer Progression ◽  
Rho Gtpases ◽  
Current Knowledge ◽  
Small Gtpases ◽  
Cell Morphogenesis ◽  
New Paradigm ◽  
Direct Involvement ◽  
Cell Locomotion ◽  
Human Cancers ◽  
Cytoskeletal Dynamics

Involvement of Rho GTPases in cancer has been a matter of debate since the identification of the first members of this branch of the Ras superfamily of small GTPases. The Rho GTPases were ascribed important roles in the cell, although these were restricted to regulation of cytoskeletal dynamics, cell morphogenesis, and cell locomotion, with initially no clear indications of direct involvement in cancer progression. This paradigm has been challenged by numerous observations that Rho-regulated pathways are often dysregulated in cancers. More recently, identification of point mutants in the Rho GTPases Rac1, RhoA, and Cdc42 in human tumors has finally given rise to a new paradigm, and we can now state with confidence that Rho GTPases serve as oncogenes in several human cancers. This article provides an exposé of current knowledge of the roles of activated Rho GTPases in cancers.

scholarly journals Experimental Study of the Features of Moral Concepts and Moral Regulation of Behavior of Children with Intellectual Disability

2020 ◽  
Vol 9 (2) ◽  
pp. 213-228
Author(s):  
A.M. Shcherbakova ◽  
N.S. Lykova
Keyword(s):  
Experimental Study ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Moral Dilemmas ◽  
Actual Behavior ◽  
Moral Choice ◽  
Moral Regulation ◽  
Moral Position ◽  
And Behavior ◽  
Children With Intellectual Disability

The article focuses on the problem of development of moral sphere of personality of children with intellectual disability (mild mental retardation) in the context of development of their life competence. Personal outcomes are considered as one of the most important indicators of the formation of life competence. Particular attention is paid to the moral development of children with intellectual disability. The results of an experimental study of the characteristics of moral perceptions and behavior of younger students with mental retardation of 9-10 years old brought up in different conditions - family and institutional are presented. Students of a comprehensive school with a normotypic development were also involved. The sample was 76 people. A study was made of the moral position, and on this basis the prediction of one's own behavior and the behavior of others in solving moral dilemmas, as well as the actual behavior of the child in a situation of moral choice.

scholarly journals Regulation of Rho GTPases in the Vasculature by Cullin3-Based E3 Ligase Complexes

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabienne Podieh ◽  
Peter L. Hordijk
Keyword(s):  
Rho Gtpases ◽  
Vascular Function ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
E3 Ligase ◽  
Small Gtpases ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Ubiquitin E3 Ligase ◽  
Cytoskeletal Dynamics

Cullin3-based ubiquitin E3 ligases induce ubiquitination of substrates leading to their proteasomal or lysosomal degradation. BTB proteins serve as adaptors by binding to Cullin3 and recruiting substrate proteins, which enables specific recognition of a broad spectrum of targets. Hence, Cullin3 and its adaptors are involved in myriad cellular processes and organ functions. Cullin3-based ubiquitin E3 ligase complexes target small GTPases of the Rho subfamily, which are key regulators of cytoskeletal dynamics and cell adhesion. In this mini review, we discuss recent insights in Cullin3-mediated regulation of Rho GTPases and their impact on cellular function and disease. Intriguingly, upstream regulators of Rho GTPases are targeted by Cullin3 complexes as well. Thus, Rho GTPase signaling is regulated by Cullin3 on multiple levels. In addition, we address current knowledge of Cullin3 in regulating vascular function, focusing on its prominent role in endothelial barrier function, angiogenesis and the regulation of blood pressure.

Sexuality, intellectual disability, and human rights legislation

2016 ◽  
Vol 46 (4) ◽  
pp. 504-516 ◽  
Author(s):  
Anne Kramers-Olen
Keyword(s):  
Human Rights ◽  
Intellectual Disability ◽  
Intellectual Disabilities ◽  
Intimate Relationships ◽  
Current Knowledge ◽  
Sexual Expression ◽  
Central Feature ◽  
Sexual Autonomy ◽  
Health Practitioners ◽  
Rights Issues

Sexuality constitutes a central feature of what it is to be human, yet health practitioners, families, and caregivers frequently perceive romantic and sexually intimate relationships among persons with intellectual disabilities to be inappropriate tending to regard such individuals as either ‘asexual’ or ‘hyper-sexed’. A number of myths, stereotypes, and prejudices intersect in a manner that has deleterious consequences for persons with intellectual disabilities. This article reviews the literature on sexuality and barriers to sexual expression among persons with intellectual disabilities. Relevant legislative frameworks and human rights issues, in particular, the tensions between protecting persons with intellectual disabilities from exploitation, and the promotion of sexual autonomy also receive consideration. In addition, the article explores issues relating to competency to consent to sexual acts and concludes with a synthesis of the current knowledge.

Rho GTPase Activating Protein 9 (ARHGAP9) in Human Cancers

2021 ◽  
Vol 16 ◽  
Author(s):  
Wenping Song ◽  
Jinhua Chen ◽  
Shuolei Li ◽  
Ding Li ◽  
Yongna Zhang ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Cancer Progression ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Current Knowledge ◽  
Clinical Success ◽  
Predictive Biomarker ◽  
Migration And Invasion ◽  
Targeted Drugs ◽  
Gtpase Activating Protein

Background: In recent years, targeted therapy combined with traditional chemoradiotherapy and surgery has brought new opportunities for cancer treatment. However, the complex characteristics of cancer, such as heterogeneity and diversity, limit the clinical success of targeted drugs. The discovery of new cancer targets and deepening the understanding of their functional mechanisms will bring additional promising application prospects for the research and development of personalized cancer-targeted drugs. Objective: This study aimed to summarize the role of the Rho GTPase activating protein 9 (ARHGAP9) gene in tumorigenesis and development to discover therapeutic targets for cancer in the future. Methods: For this review, we collected patents from the databases of Espacenet and WIPO and articles from PubMed that were related to the ARHGAP9 gene. Results: Genetic/epigenetic variations and abnormal expression of the ARHGAP9 gene are closely associated with a variety of diseases, including cancer. ARHGAP9 can inactivate Rho GTPases by hydrolyzing GTP into GDP and regulate cancer cellular events, including proliferation, differentiation, apoptosis, migration and invasion, by inhibiting JNK/ERK/p38 and PI3K/AKT signaling pathways. In addition to reviewing these mechanisms, we assessed various patents on ARHGAP9 to determine whether ARHGAP9 might be used as a predictive biomarker for diagnosis/prognosis evaluation and a druggable target for cancer treatment. Conclusion: In this review, the current knowledge of ARHGAP9 in cancer is summarized with an emphasis on its molecular function, regulatory mechanism and disease implications. Its characterization is crucial to understanding its important roles during different stages of cancer progression and therapy as a predictive biomarker and/or target.

Mental health in intellectual disability

2018 ◽  
pp. 265-272
Author(s):  
Sabyasachi Bhaumik ◽  
Dasari Mohan Michael ◽  
Reza Kiani ◽  
Avinash Hiremath ◽  
Shweta Gangavati ◽  
...  
Keyword(s):  
Mental Health ◽  
Intellectual Disability ◽  
Mental Health Problems ◽  
Current Knowledge ◽  
Premature Mortality ◽  
Health Problems ◽  
Physical And Mental Health ◽  
Middle Income ◽  
Middle Income Countries

This chapter focuses on the current knowledge in public health for people with intellectual disability and recognizes the extent of health inequalities these individuals experience. The prevalence of intellectual disability worldwide is discussed with special emphasis on the prevalence of mental health problems. Also highlighted are the population health characteristics, including physical and mental health problems. The issue of barriers to accessibility and the possible reasons are discussed. There is a section on premature mortality of people with intellectual disability and measures to improve the health status for this marginalized population. Recent initiatives, including prevention strategies and health promotional aspects, are discussed and solutions suggested, including those for low-and-middle income countries (LAMICs)emphasized. Training aspects to improve quality of health care in LAMICs is highlighted with the recognition of limitations in creating a sustainable transformation of services unless they are backed by authorities.

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