Origins Of Abnormalities Research Articles

Imaging the development of the human craniofacial arterial system - an experimental study.

The process of vascular development is essential for shaping complex craniofacial structures. Investigating the interplay between vascular development and orofacial morphogenesis holds critical importance in clinical practice and contributes to advancing our comprehension of (vascular) developmental biology. New insights into specific vascular developmental pathways will have far-reaching implications across various medical disciplines, enhancing clinical understanding, refining surgical techniques, and elucidating the origins of congenital abnormalities. Embryonic development of the craniofacial vasculature remains, however, under-exposed in the current literature. We imaged and created 3-dimensional (D) reconstructed images of the craniofacial arterial system from two early-stage human embryonic samples. The aim of this study was to investigate the vascular development of the craniofacial region in early-stage human embryos, with a focus on understanding the interplay between vascular development and orofacial morphogenesis. Reconstructions (3-D) were generated from high-resolution diffusible iodine-based contrast-enhanced computed tomography (diceCT) images, enabling visualization of the orofacial arterial system in human embryonic samples of Carnegie stages (CS) 14 and 18 from the Dutch Fetal Biobank, corresponding to weeks 7 and 8.5 of gestation. From two human embryonic samples (ages CS 14 and 18), the vascular development of the orofacial region at two different stages of development was successfully stained with B-Lugol and imaged using a micro-computed tomography (micro-CT) scanner with resolutions of 2.5-μm and 9-μm voxel sizes, respectively. Additionally, educational 3-D reconstructions of the orofacial vascular system were generated using AMIRA 2021.2 software. Micro-CT imaging is an effective strategy for high-resolution visualization of vascular development of the orofacial region in human embryonic samples. The generated interactive 3-D educational models facilitate better understanding of the development of orofacial structures.

Haplotype-aware inference of human chromosome abnormalities

Extra or missing chromosomes-a phenomenon termed aneuploidy-frequently arise during human meiosis and embryonic mitosis and are the leading cause of pregnancy loss, including in the context of in vitro fertilization (IVF). While meiotic aneuploidies affect all cells and are deleterious, mitotic errors generate mosaicism, which may be compatible with healthy live birth. Large-scale abnormalities such as triploidy and haploidy also contribute to adverse pregnancy outcomes, but remain hidden from standard sequencing-based approaches to preimplantation genetic testing for aneuploidy (PGT-A). The ability to reliably distinguish meiotic and mitotic aneuploidies, as well as abnormalities in genome-wide ploidy, may thus prove valuable for enhancing IVF outcomes. Here, we describe a statistical method for distinguishing these forms of aneuploidy based on analysis of low-coverage whole-genome sequencing data, which is the current standard in the field. Our approach overcomes the sparse nature of the data by leveraging allele frequencies and linkage disequilibrium (LD) measured in a population reference panel. The method, which we term LD-informed PGT-A (LD-PGTA), retains high accuracy down to coverage as low as 0.05 × and at higher coverage can also distinguish between meiosis I and meiosis II errors based on signatures spanning the centromeres. LD-PGTA provides fundamental insight into the origins of human chromosome abnormalities, as well as a practical tool with the potential to improve genetic testing during IVF.

Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities.

Simple SummaryChromosome instability (CIN) is characterized by an increased accumulation of numerical and structural changes in chromosomes and is a common feature of solid tumors and some hematological malignancies. CIN has been extensively linked to tumorigenesis, cancer progression, and tumor resistance. However, in recent years CIN phenotypes are increasingly being harnessed for therapeutic purposes. In this review, we describe the origins of structural CIN phenotypes and highlight novel pathways for their resolution. We also discuss how CIN can be avoided or enhanced and the implications of these pathways for cell survival and thus, cancer treatments.Chromosomal instability (CIN) refers to an increased rate of acquisition of numerical and structural changes in chromosomes and is considered an enabling characteristic of tumors. Given its role as a facilitator of genomic changes, CIN is increasingly being considered as a possible therapeutic target, raising the question of which variables may convert CIN into an ally instead of an enemy during cancer treatment. This review discusses the origins of structural chromosome abnormalities and the cellular mechanisms that prevent and resolve them, as well as how different CIN phenotypes relate to each other. We discuss the possible fates of cells containing structural CIN, focusing on how a few cell duplication cycles suffice to induce profound CIN-mediated genome alterations. Because such alterations can promote tumor adaptation to treatment, we discuss currently proposed strategies to either avoid CIN or enhance CIN to a level that is no longer compatible with cell survival.

Origin of the anomalously low Raman exponents in single molecule magnets

The Raman exponent of single-molecular magnetic relaxation may take various unexpected values because of rich phonon spectrum and spin-phonon coupling of molecular crystals. We systematically examine the origins of different abnormalities, and clarify misunderstandings in the past, particularly the appropriateness of the fitting procedures for the exponents. We find that exponential laws raised by optical phonons can yield spurious power laws with low exponents. This observation indicates long-standing misunderstandings for origins of low Raman exponents in a large bulk of single-molecule magnets. Resulting from spin-lattice coupling with optical modes, presence of these exponents suggests the importance of the local dynamical environment for the magnetic relaxation in this regime.

Gene-environment interactions: aligning birth defects research with complex etiology.

Developmental biologists rely on genetics-based approaches to understand the origins of congenital abnormalities. Recent advancements in genomics have made it easier than ever to investigate the relationship between genes and disease. However, nonsyndromic birth defects often exhibit non-Mendelian inheritance, incomplete penetrance or variable expressivity. The discordance between genotype and phenotype indicates that extrinsic factors frequently impact the severity of genetic disorders and vice versa. Overlooking gene-environment interactions in birth defect etiology limits our ability to identify and eliminate avoidable risks. We present mouse models of sonic hedgehog signaling and craniofacial malformations to illustrate both the importance of and current challenges in resolving gene-environment interactions in birth defects. We then prescribe approaches for overcoming these challenges, including use of genetically tractable and environmentally responsive in vitro systems. Combining emerging technologies with molecular genetics and traditional animal models promises to advance our understanding of birth defect etiology and improve the identification and protection of vulnerable populations.

Quantification of gene expression patterns to reveal the origins of abnormal morphogenesis

The earliest developmental origins of dysmorphologies are poorly understood in many congenital diseases. They often remain elusive because the first signs of genetic misregulation may initiate as subtle changes in gene expression, which are hard to detect and can be obscured later in development by secondary effects. Here, we develop a method to trace back the origins of phenotypic abnormalities by accurately quantifying the 3D spatial distribution of gene expression domains in developing organs. By applying Geometric Morphometrics to 3D gene expression data obtained by Optical Projection Tomography, we determined that our approach is sensitive enough to find regulatory abnormalities that have never been detected previously. We identified subtle but significant differences in the gene expression of a downstream target of a Fgfr2 mutation associated with Apert syndrome, demonstrating that these mouse models can further our understanding of limb defects in the human condition. Our method can be applied to different organ systems and models to investigate the etiology of malformations.

Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia.

Abnormalities in the kynurenine pathway (KP) of tryptophan degradation, leading to the dysfunction of neuroactive KP metabolites in the brain, have been implicated in the pathophysiology of schizophrenia (SZ). One plausible mechanism involves dysregulation of various pro-inflammatory cytokines associated with the disease, which affect indoleamine-2,3-dioxygenase (IDO), a key enzyme for tryptophan to kynurenine conversion. In order to test this hypothesis directly, we measured plasma levels of the major KP metabolites kynurenine and kynurenic acid (KYNA), as well as four major cytokines, in a sample of 106 SZ patients and 104 control participants. In contrast to the replicable findings of elevation of KYNA in the central nervous system in SZ, plasma levels of KYNA were significantly lower in SZ compared to controls (p = .004). Kynurenine levels were significantly correlated with levels of interferon-γ (p < .001), which is involved in the regulation of IDO, in both patients and controls. However, although patients had higher levels of interleukin-6 (IL-6) compared to controls (p = .012), IL-6 levels were not correlated with kynurenine or KYNA, and did not explain group differences in KYNA. Based on the lack of evidence that pro-inflammatory cytokines were significantly related to the KP abnormality in SZ despite an adequate sample size, further studies must consider alternative hypotheses to identify the origins of the KP abnormalities in SZ.

Genome stability of programmed stem cell products.

Inherited and acquired genomic abnormalities are known to cause genetic diseases and contribute to cancer formation. Recent studies demonstrated a substantial mutational load in mouse and human embryonic and induced pluripotent stem cells (ESCs and iPSCs). Single nucleotide variants, copy number variations, and larger chromosomal abnormalities may influence the differentiation capacity of pluripotent stem cells and the functionality of their derivatives in disease modeling and drug screening, and are considered a serious risk for cellular therapies based on ESC or iPSC derivatives. This review discusses the types and origins of different genetic abnormalities in pluripotent stem cells, methods for their detection, and the mechanisms of development and enrichment during reprogramming and culture expansion.

Radiation signature on exposed cells: Relevance in dose estimation.

The radiation is considered as a double edged sword, as its beneficial and detrimental effects have been demonstrated. The potential benefits are being exploited to its maximum by adopting safe handling of radionuclide stipulated by the regulatory agencies. While the occupational workers are monitored by personnel monitoring devices, for general publics, it is not a regular practice. However, it can be achieved by using biomarkers with a potential for the radiation triage and medical management. An ideal biomarker to adopt in those situations should be rapid, specific, sensitive, reproducible, and able to categorize the nature of exposure and could provide a reliable dose estimation irrespective of the time of the exposures. Since cytogenetic markers shown to have many advantages relatively than other markers, the origins of various chromosomal abnormalities induced by ionizing radiations along with dose-response curves generated in the laboratory are presented. Current status of the gold standard dicentric chromosome assay, micronucleus assay, translocation measurement by fluorescence in-situ hybridization and an emerging protein marker the γ-H2AX assay are discussed with our laboratory data. With the wide choice of methods, an appropriate assay can be employed based on the net.

The different molecular forms of urine neutrophil gelatinase-associated lipocalin present in dogs with urinary diseases.

BackgroundNeutrophil gelatinase-associated lipocalin (NGAL) is a useful biomarker for the early prediction of renal diseases. NGAL may exist as monomer, dimer and/or NGAL/MMP-9 complex forms in humans. In this study, the existence of various forms of NGAL in urine (uNGAL) was determined and whether these forms are related to the different urinary diseases found in dogs is further discussed.ResultsEighty-one urine samples from dogs with different forms of renal disease (41), pyuria (19) and a number of non-renal related diseases (10), as well as healthy dogs (11), were collected. uNGAL concentrations and their molecular forms in dogs were measured by ELISA and Western blot analysis, respectively. The uNGAL concentrations of dogs with pyuria (median: 15.35 ng/mL) were significantly higher than those of the healthy control animals (median: 3.92 ng/mL) (p < 0.01), but lower than those of dogs with renal diseases (median: 23.77 ng/mL). Each NGAL molecular form could be detected in dog urine. In particular, monomer was detected more frequently in patients with renal disease than those with non-renal diseases; while the dimer form appeared in a significantly higher percentage of cases with pyuria compared to those without pyuria. The NGAL/MMP-9 complex was found to exist not only in the patients with cystitis, but also in the cases with renal injury.ConclusionDifferent molecular forms of uNGAL can indicate different origins of the urinary abnormalities. Determining the molecular forms of uNGAL present in diseased dogs may provide clinical workers with a tool that will help the early and more precise detection of different urinary diseases.

Current Challenges in Pediatric Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) in the pediatric population is associated with a variety of underlying diseases and causes, significantly morbidity and mortality. In the majority of patients, PAH in children is idiopathic or associated with congenital heart disease (CHD), with pulmonary hypertension (PH) associated with connective tissue disease, a rare cause in children. Classification of pediatric PH has generally followed the WHO classification, but recognition of the importance of fetal origins of PH and developmental abnormalities have led to the formation of a new pediatric-specific classification. Incidence data from the Netherlands has revealed an annual incidence and point prevalence of 0.7 and 4.4 for idiopathic PAH and 2.2 and 15.6 for associated pulmonary arterial hypertension-CHD cases per million children. Although the treatment with new selective pulmonary vasodilators offers hemodynamic and functional improvement in pediatric populations, the treatments in children largely depend on results from evidence-based adult studies and experience of clinicians treating children. A recent randomized clinical trial of sildenafil and its long-term extension has led to disparate recommendations in the United States and Europe.

Bloomsbury report on mouse embryo phenotyping: recommendations from the IMPC workshop on embryonic lethal screening.

Identifying genes that are important for embryo development is a crucial first step towards understanding their many functions in driving the ordered growth, differentiation and organogenesis of embryos. It can also shed light on the origins of developmental disease and congenital abnormalities. Current international efforts to examine gene function in the mouse provide a unique opportunity to pinpoint genes that are involved in embryogenesis, owing to the emergence of embryonic lethal knockout mutants. Through internationally coordinated efforts, the International Knockout Mouse Consortium (IKMC) has generated a public resource of mouse knockout strains and, in April 2012, the International Mouse Phenotyping Consortium (IMPC), supported by the EU InfraCoMP programme, convened a workshop to discuss developing a phenotyping pipeline for the investigation of embryonic lethal knockout lines. This workshop brought together over 100 scientists, from 13 countries, who are working in the academic and commercial research sectors, including experts and opinion leaders in the fields of embryology, animal imaging, data capture, quality control and annotation, high-throughput mouse production, phenotyping, and reporter gene analysis. This article summarises the outcome of the workshop, including (1) the vital scientific importance of phenotyping embryonic lethal mouse strains for basic and translational research; (2) a common framework to harmonise international efforts within this context; (3) the types of phenotyping that are likely to be most appropriate for systematic use, with a focus on 3D embryo imaging; (4) the importance of centralising data in a standardised form to facilitate data mining; and (5) the development of online tools to allow open access to and dissemination of the phenotyping data.

Innovative Approach to Investigating the Microstructure of Calcified Tissues Using Specular Reflectance Fourier Transform-Infrared Microspectroscopy and Discriminant Analysis

Although bone fracture has become a serious global health issue, current clinical assessments of fracture risk based on bone mineral density are unable to accurately predict whether an individual is likely to suffer a fracture. There is increasing recognition that the chemical structure and composition, or microstructure, of mineralized tissues has an important role to play in determining the fracture resistance of bone. The objective of this preliminary study was to evaluate the use of specular reflectance Fourier transform infrared (SR FT-IR) microspectroscopy in conjunction with discriminant analysis as an innovative technique for providing future insights into the origins of orthopedic abnormalities. The impetus for this approach was that SR FT-IR microspectroscopy would offer several advantages over conventional transmission methods. Bone samples were obtained from young racehorses at known fracture predilection sites and spectra were successfully obtained from calcified cartilage and subchondral bone for the first time. By applying discriminant analysis to the spectral data set in biologically relevant regions, microstructural differences between groups of individuals were found to be related to features associated with both the mineral and organic components of the bone. The preliminary findings also suggest that differences in bone microstructure may exist between healthy individuals of the same age, raising important questions around the normal limits of individual variation and whether individuals may be predisposed to later fracture as a result of detrimental microstructural changes during early growth and development.

Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models.

The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as ‘Risk factors for schizophrenia—all roads lead to dopamine' or ‘The dopamine hypothesis of schizophrenia—the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this disease is at present unknown as such early brain alterations are rarely examined. Although it is premature to conclude that such mechanisms could be operating in other developmental animal models for schizophrenia, our convergent data have led us to propose that rather than all roads leading to DA, perhaps, this may be where they start.

The EEG in E200K familial CJD: relation to MRI patterns

The aim of the study was to examine the relationship between EEG abnormalities and the pattern of MRI changes in familial Creutzfeldt-Jakob Disease (fCJD) patients with E200K mutation. As part of a controlled, prospective study, 13 E200K fCJD patients underwent comprehensive evaluations, with EEG and an extensive MRI protocol that included one of the most prion-disease sensitive sequences, diffusion-weighted imaging (DWI). The relationship between EEG abnormalities and the pattern of DWI hyperintensities was examined. EEG demonstrated the classical CJD finding of PSWC (periodic sharp wave complexes) in five patients (38%) while in eight patients (62%) the EEG showed only slow activity. Six patients showed the typical cortical changes on MRI, and in five of them (83%) concordance between the MRI and the EEG was found. Five patients had isolated basal ganglia involvement per MRI, and in two of them (40%) concordance between the MRI and the EEG laterality was found. In the remaining two patients MRI did not show any changes suggesting CJD and EEG showed focal slow activity. The EEG of our E200K fCJD patients appears similar to that of the largest prion disease patient group, sporadic CJD (sCJD). EEG abnormalities in E200K fCJD appear to correlate mainly with cortical pathology, as revealed by DWI, rather than basal ganglia pathology. The observation that PSWC abnormalities reflect cortical rather than basal ganglia pathology is significant with respect to theories of the origins of EEG abnormalities in prion disease.

Believing in the Patient's Capacity to Know His Mind: A Psychoanalytic Case Study of Fibromyalgia

Fibromyalgia is currently viewed as a disorder of pain and stress processing in the central nervous system. Various stressors in combination with constitutional and genetic factors can trigger the syndrome, and the way the brain processes stress has been linked to early relationship experiences. The author discusses the relationship between fibromyalgia and attachment dynamics in the context of a clinical analysis, and draws inferences about the intrapsychic origins of functional brain abnormalities seen in neuroimaging studies. The patient had core deficits in his capacity to mentalize and self-soothe, and catastrophized somatic sensory information. Because his capacity for self-reflective mentalization was so limited, interpretation of underlying conflict-ridden affect at first did little good. The analyst's most productive intervention was a consistent meta-communication of belief in the patient's capacity to know his own mind.

Quantitative proteomic analysis of primary neurons reveals diverse changes in synaptic protein content in fmr1 knockout mice.

Fragile X syndrome (FXS) is a common inherited form of mental retardation that is caused, in the vast majority of cases, by the transcriptional silencing of a single gene, fmr1. The encoded protein, FMRP, regulates mRNA translation in neuronal dendrites, and it is thought that changes in translation-dependent forms of synaptic plasticity lead to many symptoms of FXS. However, little is known about the potentially extensive changes in synaptic protein content that accompany loss of FMRP. Here, we describe the development of a high-throughput quantitative proteomic method to identify differences in synaptic protein expression between wild-type and fmr1-/- mouse cortical neurons. The method is based on stable isotope labeling by amino acids in cell culture (SILAC), which has been used to characterize differentially expressed proteins in dividing cells, but not in terminally differentiated cells because of reduced labeling efficiency. To address the issue of incomplete labeling, we developed a mathematical method to normalize protein ratios relative to a reference based on the labeling efficiency. Using this approach, in conjunction with multidimensional protein identification technology (MudPIT), we identified >100 proteins that are up- or down-regulated. These proteins fall into a variety of functional categories, including those regulating synaptic structure, neurotransmission, dendritic mRNA transport, and several proteins implicated in epilepsy and autism, two endophenotypes of FXS. These studies provide insights into the potential origins of synaptic abnormalities in FXS and a demonstration of a methodology that can be used to explore neuronal protein changes in neurological disorders.

The Tom Oppe Lecture: Behavioural phenotypes and child psychiatry

The concept of a behavioural phenotype was first introduced by Nyhan (1972) when he described a characteristic behaviour of self‐mutilation in Lesch‐Nyhan‐Syndrome. Later, Flint and Yule (1994) pointed out that a behavioural phenotype is a characteristic pattern of motor, cognitive, linguistic and social abnormalities that is consistently associated with a biological disorder. In some instances the behavioural phenotype may represent a psychiatric disorder, in others there may be behaviours that usually will not be regarded as a psychiatric disorder.Dykens (1995) added that a behavioural phenotype may best be described as the heightened probability that people with a given syndrome will be characterized by certain behavioural sequelae. The implications of this are (i) that there is a certain amount of within‐syndrome variability, (ii) that there is total vs. partial specificity of certain behaviours, (iii) that behavioural phenotypes relate to various behavioural domains, (iv) that behavioural phenotypes have indirect effects on the behaviour of caretakers, and (v) that developmental and contextual factors in addition to genetic factors contribute to behavioural phenotypes (Hodapp &amp; Dykens, 2007). The rather recent interest in the concept of behavioural phenotypes has renewed the interest of Child and Adolescent Psychiatry in intellectual disability issues that had been lost for decades. It also increased interest in the genetic origins of mental disorders and behavioural abnormalities with an interaction of two major recent scientific developments in the field. One of these trends is represented by the rapid progress in molecular biology that has led to a better understanding of the genetic mechanisms contributing to psychopathology. The other trend is based on the development of more and more refined instruments for the dimensional assessment of adaptive and maladaptive behaviours which have supplemented the classical categorical approach of assessment in child psychopathology. With this theoretical underpinning, the study of behavioural phenotypes has become an attractive research domain in child and adolescent psychiatry. In addition, there are also practical implications in terms of improving communication among experts and lay‐person both on assessment and counselling.

Muscle and reflex changes with varying joint angle in hemiparetic stroke

BackgroundDespite intensive investigation, the origins of the neuromuscular abnormalities associated with spasticity are not well understood. In particular, the mechanical properties induced by stretch reflex activity have been especially difficult to study because of a lack of accurate tools separating reflex torque from torque generated by musculo-tendinous structures. The present study addresses this deficit by characterizing the contribution of neural and muscular components to the abnormally high stiffness of the spastic joint.MethodsUsing system identification techniques, we characterized the neuromuscular abnormalities associated with spasticity of ankle muscles in chronic hemiparetic stroke survivors. In particular, we systematically tracked changes in muscle mechanical properties and in stretch reflex activity during changes in ankle joint angle. Modulation of mechanical properties was assessed by applying perturbations at different initial angles, over the entire range of motion (ROM). Experiments were performed on both paretic and non-paretic sides of stroke survivors, and in healthy controls.ResultsBoth reflex and intrinsic muscle stiffnesses were significantly greater in the spastic/paretic ankle than on the non-paretic side, and these changes were strongly position dependent. The major reflex contributions were observed over the central portion of the angular range, while the intrinsic contributions were most pronounced with the ankle in the dorsiflexed position.ConclusionIn spastic ankle muscles, the abnormalities in intrinsic and reflex components of joint torque varied systematically with changing position over the full angular range of motion, indicating that clinical perceptions of increased tone may have quite different origins depending upon the angle where the tests are initiated.Furthermore, reflex stiffness was considerably larger in the non-paretic limb of stroke patients than in healthy control subjects, suggesting that the non-paretic limb may not be a suitable control for studying neuromuscular properties of the ankle joint.Our findings will help elucidate the origins of the neuromuscular abnormalities associated with stroke-induced spasticity.

Developmental origins of blood pressure abnormalities

Developmental origins of blood pressure abnormalities