scholarly journals Modeling autism-associated SHANK3 deficiency using human cortico-striatal organoids generated from single neural rosettes

2021 ◽  
Author(s):  
Yueqi Wang ◽  
Simone Chiola ◽  
Guang Yang ◽  
Chad Russell ◽  
Celeste J. Armstrong ◽  
...  
Keyword(s):  
Developmental Stages ◽  
Experimental Models ◽  
New Method ◽  
Deletion Syndrome ◽  
Striatal Neurons ◽  
Genetic Abnormality ◽  
Cell Lineages ◽  
Mural Cells ◽  
Pathological Conditions ◽  
Clustered Protocadherins

SUMMARYOur understanding of the human brain is limited by the lack of experimental models to mechanistically probe the properties of brain cells at different developmental stages under normal and pathological conditions. We developed a new method for generating human cortico-striatal organoids from stem cell-derived single neural rosettes (SNRs) and used it to investigate cortico-striatal development and deficits caused by the deficiency of an autism- and intellectual disability-associated gene SHANK3. We show that SNR-derived organoids consist of different cortico-striatal cells, including pallial and subpallial progenitors, primary cortical and striatal neurons, interneurons, as well as macroglial and mural cells. We also demonstrate that neurons in SNR-derived organoids are predictably organized, functionally mature, and capable of establishing functional neural networks. Interestingly, we found that the cellular and electrophysiological deficits in SHANK3-deficient SNR-derived organoids are dependent on the level of SHANK3 expression and that organoids with complete hemizygous SHANK3 deletion have disrupted expression of several clustered protocadherins and multiple primate-specific zinc-finger genes. Together, this study describes a new method for using SNRs to generate organoids, provides new insights into the cell lineages associated with human cortico-striatal development, and identifies specific molecular pathways disrupted by hemizygous SHANK3 deletion, which is the most common genetic abnormality detected in patients with 22q13 deletion syndrome.

Psychosocial Risks and Management for Children and Adolescents With 22q11.2 Deletion Syndrome

2019 ◽  
Vol 4 (4) ◽  
pp. 633-640 ◽  
Author(s):  
Canice E. Crerand ◽  
Ari N. Rabkin
Keyword(s):  
Cognitive Abilities ◽  
Psychotic Disorders ◽  
Developmental Stages ◽  
Early Adulthood ◽  
22Q11.2 Deletion Syndrome ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Psychosocial Risks ◽  
Empirically Supported ◽  
Specific Education

Purpose This article reviews the psychosocial risks associated with 22q11.2 deletion syndrome, a relatively common genetic condition associated with a range of physical and psychiatric problems. Risks associated with developmental stages from infancy through adolescence and early adulthood are described, including developmental, learning, and intellectual disabilities as well as psychiatric disorders including anxiety, mood, and psychotic disorders. Other risks related to coping with health problems and related treatments are also detailed for both affected individuals and their families. Conclusion The article ends with strategies for addressing psychosocial risks including provision of condition-specific education, enhancement of social support, routine assessment of cognitive abilities, regular mental health screening, and referrals for empirically supported psychiatric and psychological treatments.

scholarly journals Corticostriatal Plastic Changes in Experimental L-DOPA-Induced Dyskinesia

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Veronica Ghiglieri ◽  
Vincenza Bagetta ◽  
Valentina Pendolino ◽  
Barbara Picconi ◽  
Paolo Calabresi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Experimental Models ◽  
Striatal Neurons ◽  
Da Receptors ◽  
Electrophysiological Studies ◽  
Plastic Changes ◽  
Stimulation Of

In Parkinson’s disease (PD), alteration of dopamine- (DA-) dependent striatal functions and pulsatile stimulation of DA receptors caused by the discontinuous administration of levodopa (L-DOPA) lead to a complex cascade of events affecting the postsynaptic striatal neurons that might account for the appearance of L-DOPA-induced dyskinesia (LID). Experimental models of LID have been widely used and extensively characterized in rodents and electrophysiological studies provided remarkable insights into the inner mechanisms underlying L-DOPA-induced corticostriatal plastic changes. Here we provide an overview of recent findings that represent a further step into the comprehension of mechanisms underlying maladaptive changes of basal ganglia functions in response to L-DOPA and associated to development of LID.

scholarly journals The Role of Immune-Related miRNAs in the Pathology of Kidney Transplantation

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1198
Author(s):  
Emanuela Boštjančič ◽  
Željka Večerić-Haler ◽  
Nika Kojc
Keyword(s):  
Immune Response ◽  
Kidney Transplantation ◽  
Kidney Diseases ◽  
Experimental Models ◽  
Regulatory Rna ◽  
Limited Data ◽  
Pathological Conditions ◽  
Monitoring Response ◽  
Disease Specific

MicroRNAs (miRNAs) are members of the non-coding regulatory RNA family that play pivotal roles in physiological and pathological conditions, including immune response. They are particularly interesting as promising therapeutic targets, prognostic and diagnostic markers due to their easy detection in body fluids and stability. There is accumulating evidence that different miRNAs provide disease-specific signatures in liquid samples of distinct kidney injuries. Using experimental models and human samples, there have been numerous suggestions that immune-related miRNAs are also important contributors to the development of different kidney diseases as well as important markers for monitoring response after kidney transplantation. However, there are limited data for understanding their function in the molecular pathways of allograft pathologies. In our review, we focused on microRNAs that are related to different aspects of immune response after kidney transplantation.

scholarly journals Clonal Heterogeneity in the Neuronal and Glial Differentiation of Dental Pulp Stem/Progenitor Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Fraser I. Young ◽  
Vsevolod Telezhkin ◽  
Sarah J. Youde ◽  
Martin S. Langley ◽  
Maria Stack ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Dental Pulp ◽  
Experimental Models ◽  
Cellular Heterogeneity ◽  
Striatal Neurons ◽  
Cord Injury ◽  
Clonal Cultures ◽  
Important Challenge ◽  
A Cell

Cellular heterogeneity presents an important challenge to the development of cell-based therapies where there is a fundamental requirement for predictable and reproducible outcomes. Transplanted Dental Pulp Stem/Progenitor Cells (DPSCs) have demonstrated early promise in experimental models of spinal cord injury and stroke, despite limited evidence of neuronal and glial-like differentiation after transplantation. Here, we report, for the first time, on the ability of single cell-derived clonal cultures of murine DPSCs to differentiatein vitrointo immature neuronal-like and oligodendrocyte-like cells. Importantly, only DPSC clones with high nestin mRNA expression levels were found to successfully differentiate into Map2 and NF-positive neuronal-like cells. Neuronally differentiated DPSCs possessed a membrane capacitance comparable with primary cultured striatal neurons and small inward voltage-activated K+but not outward Na+currents were recorded suggesting a functionally immature phenotype. Similarly, only high nestin-expressing clones demonstrated the ability to adopt Olig1, Olig2, and MBP-positive immature oligodendrocyte-like phenotype. Together, these results demonstrate that appropriate markers may be used to provide an early indication of the suitability of a cell population for purposes where differentiation into a specific lineage may be beneficial and highlight that further understanding of heterogeneity within mixed cellular populations is required.

scholarly journals Mapping morphological malformation to genetic dysfunction in blood vessel organoids with 22q11.2 Deletion Syndrome

2021 ◽  
Author(s):  
Siyu He ◽  
Cong Xu ◽  
Yeh-Hsing Lao ◽  
Shradha Chauhan ◽  
Yang Xiao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessel ◽  
Single Cell ◽  
22Q11.2 Deletion Syndrome ◽  
Vascular Network ◽  
Deletion Syndrome ◽  
22Q11.2 Deletion ◽  
Mural Cells ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

DiGeorge Syndrome, or 22q11.2 deletion syndrome (22q11.2 DS), is a genetic disorder caused by microdeletions in chromosome 22, impairing the function of endothelial cells (EC) and/or mural cells and leading to deficits in blood vessel development such as abnormal aortic arch morphology, tortuous retinal vessels, and tetralogy of Fallot. The mechanism by which dysfunctional endothelial cells and pericytes contribute to the vasculopathy, however, remains unknown. In this study, we used human blood vessel organoids (VOs) generated from iPSC of 22q11.2 DS patients to model the vascular malformations and genetic dysfunctions. We combined high-resolution lightsheet imaging and single-cell transcriptome analysis to link the genetic profile and vascular phenotype at the single-cell level. We developed a comprehensive analytical methodology by integrating deep learning-mediated blood vessel segmentation, network graph construction, and tessellation analysis for automated morphology characterization. We report that 22q11.2DS VOs demonstrate a smaller size with increased angiogenesis/sprouting, suggesting a less stable vascular network. Overall, clinical presentations of smaller vascular diameter, less connected vasculature, and increased branch points were recapitulated in 22q11.2DS VOs. Single-cell transcriptome profiling showed heterogeneity in both 22q11.2DS and control VOs, but the former demonstrated alterations in endothelial characteristics that are organ-specific and suggest a perturbation in the vascular developmental process. Intercellular communication analysis indicated that the vascular dysfunctions in 22q11.2 deletion were due to a lower cell-cell contact and upregulated extracellular matrix organization involving collagen and fibronectin. Voronoi diagram-based tessellation analysis also indicated that the colocalization of endothelial tubes and mural cells was different between control and 22q11.2 VOs, indicating that alterations in EC and mural interactions might contribute to the deficits in vascular network formation. This study illustrates the utility of VO in revealing the pathogenesis of 22q11.2DS vasculopathy.

scholarly journals Multiomics Analysis of Neuroblastoma Cells Reveals a Diversity of Malignant Transformations

2021 ◽  
Vol 9 ◽  
Author(s):  
Milda Narmontė ◽  
Povilas Gibas ◽  
Kristina Daniūnaitė ◽  
Juozas Gordevičius ◽  
Edita Kriukienė
Keyword(s):  
Pediatric Cancer ◽  
Large Scale ◽  
Developmental Stages ◽  
Genome Structure ◽  
Neuroblastoma Cells ◽  
Cell Lineages ◽  
Therapeutic Value ◽  
Cell Type Specific ◽  
Single Base Resolution ◽  
Cell Subpopulations

Neuroblastoma (NB) is a pediatric cancer of the developing sympathetic nervous system that exhibits significant variation in the stage of differentiation and cell composition of tumors. Global loss of DNA methylation and genomic 5-hydroxymethylcytosine (5hmC) is a hallmark of human cancers. Here, we used our recently developed single-base resolution approaches, hmTOP-seq and uTOP-seq, for construction of 5hmC maps and identification of large partially methylated domains (PMDs) in different NB cell subpopulations. The 5hmC profiles revealed distinct signatures characteristic to different cell lineages and stages of malignant transformation of NB cells in a conventional and oxygen-depleted environment, which often occurs in tumors. The analysis of the cell-type-specific PMD distribution highlighted differences in global genome organization among NB cells that were ascribed to the same lineage identity by transcriptomic networks. Collectively, we demonstrated a high informativeness of the integrative epigenomic and transcriptomic research and large-scale genome structure in investigating the mechanisms that regulate cell identities and developmental stages of NB cells. Such multiomics analysis, as compared with mutational studies, open new ways for identification of novel disease-associated features which bring prognostic and therapeutic value in treating this aggressive pediatric disease.

scholarly journals The 22q11.2 Deletion Syndrome: A Gene Dosage Perspective

2006 ◽  
Vol 6 ◽  
pp. 1881-1887 ◽  
Author(s):  
Antonio Baldini
Keyword(s):  
Developmental Stages ◽  
Gene Dosage ◽  
Single Gene ◽  
22Q11.2 Deletion Syndrome ◽  
Genomic Region ◽  
Deletion Syndrome ◽  
Genomic Disorder ◽  
22Q11.2 Deletion ◽  
Developmental Context

The 22q11.2 deletion/DiGeorge syndrome is a relatively common “genomic” disorder that results from heterozygous deletion of a 3-Mbp segment of chromosome 22. Of the more than 30 genes deleted in this syndrome,TBX1is the only one that has been found to be mutated in some patients with a phenotype that is very similar to that of patients with the full deletion, suggesting thatTBX1haploinsufficiency is a major contributor to the syndrome’s phenotype. Multi- and single-gene mouse models have provided a considerable amount of information about the consequences of decreased and increased dosage of the genomic region (and in particular of theTbx1gene) on mouse embryonic development. Modified alleles ofTbx1, as well as conditional ablation strategies have been utilized to mapin vivothe tissues and developmental stages most sensitive to gene dosage. These experiments have revealed substantially different sensitivity to gene dosage in different tissues and at different times, underlying the importance of the developmental context within which gene dosage reduction occurs.

scholarly journals The Crustacean Model Parhyale hawaiensis

2021 ◽  
Author(s):  
Mathilde Paris ◽  
Carsten Wolff ◽  
Nipam Patel ◽  
Michalis Averof
Keyword(s):  
Biological Diversity ◽  
Developmental Stages ◽  
Experimental Models ◽  
Sensory Biology ◽  
Wide Range ◽  
Fertile Ground ◽  
Parhyale Hawaiensis ◽  
Terrestrial Habitats ◽  
Marine Amphipod ◽  
Transgenic Tools

Arthropods are the most abundant and diverse animals on earth. Among them, pancrustaceans are an ancient and morphologically diverse group, comprising a wide range of aquatic and semi-aquatic crustaceans as well as the insects, which emerged from crustacean ancestors to colonise most terrestrial habitats. Within insects, Drosophila stands out as one of the most powerful animal models, making major contributions to our understanding of development, physiology and behaviour. Given these attributes, crustaceans provide a fertile ground for exploring biological diversity through comparative studies. However, beyond insects, few crustaceans are developed sufficiently as experimental models to enable such studies. The marine amphipod Parhyale hawaiensis is currently the best established crustacean system, offering year-round accessibility to developmental stages, transgenic tools, genomic resources, and established genetics and imaging approaches. The Parhyale research community is small but diverse, investigating the evolution of development, regeneration, aspects of sensory biology, chronobiology, bioprocessing and ecotoxicology.

scholarly journals DNLC: differential network local consistency analysis

2019 ◽  
Vol 20 (S15) ◽  
Author(s):  
Jianwei Lu ◽  
Yao Lu ◽  
Yusheng Ding ◽  
Qingyang Xiao ◽  
Linqing Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Biological Network ◽  
Developmental Stages ◽  
Disease Status ◽  
New Method ◽  
Local Consistency ◽  
Functional Relations ◽  
Differential Network ◽  
Clinical Conditions ◽  
Local Expression

Abstract Background The biological network is highly dynamic. Functional relations between genes can be activated or deactivated depending on the biological conditions. On the genome-scale network, subnetworks that gain or lose local expression consistency may shed light on the regulatory mechanisms related to the changing biological conditions, such as disease status or tissue developmental stages. Results In this study, we develop a new method to select genes and modules on the existing biological network, in which local expression consistency changes significantly between clinical conditions. The method is called DNLC: Differential Network Local Consistency. In simulations, our algorithm detected artificially created local consistency changes effectively. We applied the method on two publicly available datasets, and the method detected novel genes and network modules that were biologically plausible. Conclusions The new method is effective in finding modules in which the gene expression consistency change between clinical conditions. It is a useful tool that complements traditional differential expression analyses to make discoveries from gene expression data. The R package is available at https://cran.r-project.org/web/packages/DNLC.

scholarly journals INVESTIGATION OF STRAIN MEASUREMENT METHOD WITH BALANCING CURRENTS

2010 ◽  
Vol 2 (1) ◽  
pp. 68-72 ◽  
Author(s):  
Ričardas Masiulionis
Keyword(s):  
Strain Gauge ◽  
Strain Measurement ◽  
Measurement Method ◽  
Experimental Models ◽  
New Method ◽  
Identification System ◽  
Security Systems ◽  
State Identification ◽  
Wide Usage

It is shown that construction state identification systems are integral part of public and local warning and security systems. Structure of construction of state identification system is proposed and analysed. It is established that in order to ensure wide usage of such systems it is necessary to solve some scientific problems. A new method for measurement of construction strain is presented. It is based on evaluation of small changes of resistance with balancing currents. Measurements methods of these days are listed and their main advantages are discussed. Structure of strain gauge and formulas for calculating code of resistance changes is presented. Computerized and experimental models are made.

Sign in / Sign up

Export Citation Format

Share Document