Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 254
Filtrar
1.
Q J Exp Psychol (Hove) ; : 17470218221074686, 2022 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-35001729

RESUMO

Our visual system is built to extract regularities in how objects within our visual environment appear in relation to each other across time and space ('visual statistical learning'). Existing research indicates that visual statistical learning is modulated by selective attention. Our attentional system prioritises information that enables behaviour; for example, animates are prioritised over inanimates (the 'animacy advantage'). The present study examined the effects of selective attention and animacy on visual statistical learning in young adults (N = 284). We tested visual statistical learning of attended and unattended information across four animacy conditions: (i) living things that can self-initiate movement (animals); (ii) living things that cannot self-initiate movement (fruits and vegetables); (iii) non-living things that can generate movement (vehicles); and (iv) non-living things that cannot generate movement (tools and kitchen utensils). We implemented a four-point confidence-rating scale as an assessment of participants' awareness of the regularities in the visual statistical learning task. There were four key findings. First, selective attention plays a critical role by modulating visual statistical learning. Second, animacy does not play a special role in visual statistical learning. Third, visual statistical learning of attended information cannot be exclusively accounted for by unconscious knowledge. Fourth, performance on the visual statistical learning task is associated with the proportion of stimuli that were named or labelled. Our findings support the notion that visual statistical learning is a powerful mechanism by which our visual system resolves an abundance of sensory input over time.

2.
Sci Rep ; 11(1): 23788, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34893624

RESUMO

To improve understanding of Alzheimer's disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p < 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-ß in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses.

3.
Cells ; 10(11)2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34831346

RESUMO

AIMS: Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis) are autosomal recessive disorders of lysosomal function that cause progressive neurodegeneration in infants and young children. Impaired hydrolysis catalysed by ß-hexosaminidase A (HexA) leads to the accumulation of GM2 ganglioside in neuronal lysosomes. Despite the storage phenotype, the role of autophagy and its regulation by mTOR has yet to be explored in the neuropathogenesis. Accordingly, we investigated the effects on autophagy and lysosomal integrity using skin fibroblasts obtained from patients with Tay-Sachs and Sandhoff diseases. RESULTS: Pathological autophagosomes with impaired autophagic flux, an abnormality confirmed by electron microscopy and biochemical studies revealing the accelerated release of mature cathepsins and HexA into the cytosol, indicating increased lysosomal permeability. GM2 fibroblasts showed diminished mTOR signalling with reduced basal mTOR activity. Accordingly, provision of a positive nutrient signal by L-arginine supplementation partially restored mTOR activity and ameliorated the cytopathological abnormalities. INNOVATION: Our data provide a novel molecular mechanism underlying GM2 gangliosidosis. Impaired autophagy caused by insufficient lysosomal function might represent a new therapeutic target for these diseases. CONCLUSIONS: We contend that the expression of autophagy/lysosome/mTOR-associated molecules may prove useful peripheral biomarkers for facile monitoring of treatment of GM2 gangliosidosis and neurodegenerative disorders that affect the lysosomal function and disrupt autophagy.

4.
Orphanet J Rare Dis ; 16(1): 431, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34649574

RESUMO

BACKGROUND: The Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study. RESULTS: At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery. CONCLUSION: Gaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability.


Assuntos
Doença de Gaucher , Doenças do Sistema Nervoso , Estudos de Coortes , Doença de Gaucher/diagnóstico , Doença de Gaucher/genética , Glucosilceramidase/genética , Humanos , Estudos Prospectivos , Estudos Retrospectivos
6.
Development ; 148(17)2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383890

RESUMO

Neural crest cells (NCCs) within the mandibular and maxillary prominences of the first pharyngeal arch are initially competent to respond to signals from either region. However, mechanisms that are only partially understood establish developmental tissue boundaries to ensure spatially correct patterning. In the 'hinge and caps' model of facial development, signals from both ventral prominences (the caps) pattern the adjacent tissues whereas the intervening region, referred to as the maxillomandibular junction (the hinge), maintains separation of the mandibular and maxillary domains. One cap signal is GATA3, a member of the GATA family of zinc-finger transcription factors with a distinct expression pattern in the ventral-most part of the mandibular and maxillary portions of the first arch. Here, we show that disruption of Gata3 in mouse embryos leads to craniofacial microsomia and syngnathia (bony fusion of the upper and lower jaws) that results from changes in BMP4 and FGF8 gene regulatory networks within NCCs near the maxillomandibular junction. GATA3 is thus a crucial component in establishing the network of factors that functionally separate the upper and lower jaws during development.


Assuntos
Padronização Corporal , Face/embriologia , Fator de Transcrição GATA3/metabolismo , Animais , Região Branquial/citologia , Região Branquial/embriologia , Região Branquial/metabolismo , Morte Celular , Proliferação de Células , Anormalidades Craniofaciais/embriologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Embrião de Mamíferos , Fator de Transcrição GATA3/genética , Regulação da Expressão Gênica no Desenvolvimento , Mandíbula/citologia , Mandíbula/embriologia , Maxila/citologia , Maxila/embriologia , Camundongos , Morfogênese , Crista Neural/citologia , Crista Neural/embriologia , Crista Neural/metabolismo
7.
Hum Mol Genet ; 30(22): 2082-2099, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34172992

RESUMO

Krabbe disease, an inherited leukodystrophy, is a sphingolipidosis caused by deficiency of ß-galactocerebrosidase: it is characterized by myelin loss, and pathological activation of macrophage/microglia and astrocytes. To define driving pathogenic factors, we explored the expression repertoire of candidate neuroinflammatory genes: upregulation of receptor interacting protein kinase 1 (Ripk1) and disease-associated microglia (DAM) genes, including Cst7 and Ch25h, correlated with severity of Krabbe disease genetically modelled in the twitcher mouse. Upregulation of Ripk1 in Iba1/Mac2-positive microglia/macrophage associated with the pathognomic hypertrophic/globoid phenotype of this disease. Widespread accumulation of ubiquitinin1 in white and grey matter co-localised with p62. In Sandhoff disease, another sphingolipid disorder, neuroinflammation, accumulation of p62 and increased Ripk1 expression was observed. The upregulated DAM genes and macrophage/microglia expression of Ripk1 in the authentic model of Krabbe disease strongly resemble those reported in Alzheimer disease associating with disturbed autophagosomal/lysosomal homeostasis. Activation of this shared molecular repertoire, suggests the potential for therapeutic interdiction at a common activation step, irrespective of proximal causation. To clarify the role of Ripk1 in the pathogenesis of Krabbe disease, we first explored the contribution of its kinase function, by intercrossing twitcher and the K45A kinase-dead Ripk1 mouse and breeding to homozygosity. Genetic ablation of Ripk1 kinase activity neither altered the neuropathological features nor the survival of twitcher mice. We conclude that Ripk1 kinase-dependent inflammatory and degenerative capabilities play no instrumental role in Krabbe disease; however, putative kinase-independent functions of Ripk1 remain formally to be explored in its molecular pathogenesis.

8.
Hum Genet ; 140(7): 1061-1076, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33811546

RESUMO

Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.


Assuntos
Anormalidades Múltiplas/genética , Caderinas/genética , Adesão Celular/genética , Anormalidades Craniofaciais/genética , Deformidades Congênitas do Pé/genética , Variação Genética/genética , Deformidades Congênitas da Mão/genética , Hipertelorismo/genética , Sequência de Aminoácidos , Movimento Celular/genética , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo
9.
Sci Adv ; 7(6)2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33547071

RESUMO

To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.

10.
Am J Hum Genet ; 108(1): 8-15, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33417889

RESUMO

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Genômica/métodos , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Genótipo , Humanos , Mutação/genética , Fenótipo
11.
Nature ; 592(7852): 86-92, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33473216

RESUMO

The anatomy of the mammalian visual system, from the retina to the neocortex, is organized hierarchically1. However, direct observation of cellular-level functional interactions across this hierarchy is lacking due to the challenge of simultaneously recording activity across numerous regions. Here we describe a large, open dataset-part of the Allen Brain Observatory2-that surveys spiking from tens of thousands of units in six cortical and two thalamic regions in the brains of mice responding to a battery of visual stimuli. Using cross-correlation analysis, we reveal that the organization of inter-area functional connectivity during visual stimulation mirrors the anatomical hierarchy from the Allen Mouse Brain Connectivity Atlas3. We find that four classical hierarchical measures-response latency, receptive-field size, phase-locking to drifting gratings and response decay timescale-are all correlated with the hierarchy. Moreover, recordings obtained during a visual task reveal that the correlation between neural activity and behavioural choice also increases along the hierarchy. Our study provides a foundation for understanding coding and signal propagation across hierarchically organized cortical and thalamic visual areas.


Assuntos
Potenciais de Ação/fisiologia , Córtex Visual/anatomia & histologia , Córtex Visual/fisiologia , Animais , Conjuntos de Dados como Assunto , Eletrofisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Luminosa , Tálamo/anatomia & histologia , Tálamo/citologia , Tálamo/fisiologia , Córtex Visual/citologia
12.
Skeletal Radiol ; 50(2): 361-369, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32734372

RESUMO

The Erlenmeyer flask deformity is a common skeletal modeling deformity, but current classification systems are binary and may restrict its utility as a predictor of associated skeletal conditions. A quantifiable 3-point system of severity classification could improve its predictive potential in disease. Ratios were derived from volumes of regions of interests drawn in 50 Gaucher's disease patients. ROIs were drawn from the distal physis to 2 cm proximal, 2 cm to 4 cm, and 4 cm to 6 cm. Width was also measured at each of these boundaries. Two readers rated these 100 femurs using a 3-point scale of severity classification. Weighted kappa indicated reliability and one-way analysis of variance characterized ratio differences across the severity scale. Accuracy analyses allowed determination of clinical cutoffs for each ratio. Pearson's correlations assessed the associations of volume and width with a shape-based concavity metric of the femur. The volume ratio incorporating the metaphyseal region from 0 to 2 cm and the diametaphyseal region at 4-6 cm was most accurate at distinguishing femurs on the 3-point scale. Receiver operating characteristic curves for this ratio indicated areas of 0.95 to distinguish normal and mild femurs and 0.93 to distinguish mild and severe femurs. Volume was moderately associated with the degree of femur concavity. The proposed volume ratio method is an objective, proficient method at distinguishing severities of the Erlenmeyer flask deformity with the potential for automation. This may have application across diseases associated with the deformity and deficient osteoclast-mediated modeling of growing bone.


Assuntos
Fêmur , Lâmina de Crescimento , Osso e Ossos , Fêmur/diagnóstico por imagem , Humanos , Radiografia , Reprodutibilidade dos Testes
13.
J Exp Med ; 218(1)2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33091110

RESUMO

α-Synuclein (α-syn) and tau aggregates are the neuropathological hallmarks of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively, although both pathologies co-occur in patients with these diseases, suggesting possible crosstalk between them. To elucidate the interactions of pathological α-syn and tau, we sought to model these interactions. We show that increased accumulation of tau aggregates occur following simultaneous introduction of α-syn mousepreformed fibrils (mpffs) and AD lysate-derived tau seeds (AD-tau) both in vitro and in vivo. Interestingly, the absence of endogenous mouse α-syn in mice reduces the accumulation and spreading of tau, while the absence of tau did not affect the seeding or spreading capacity of α-syn. These in vivo results are consistent with our in vitro data wherein the presence of tau has no synergistic effects on α-syn. Our results point to the important role of α-syn as a modulator of tau pathology burden and spreading in the brains of AD, PDD, and DLB patients.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Camundongos , Camundongos Knockout , Doença de Parkinson/genética , Doença de Parkinson/patologia , alfa-Sinucleína/genética , Proteínas tau/genética
14.
J Lipid Res ; 62: 100018, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33361282

RESUMO

Deficiency of glucocerebrosidase (GBA), a lysosomal ß-glucosidase, causes Gaucher disease. The enzyme hydrolyzes ß-glucosidic substrates and transglucosylates cholesterol to cholesterol-ß-glucoside. Here we show that recombinant human GBA also cleaves ß-xylosides and transxylosylates cholesterol. The xylosyl-cholesterol formed acts as an acceptor for the subsequent formation of di-xylosyl-cholesterol. Common mutant forms of GBA from patients with Gaucher disease with reduced ß-glucosidase activity were similarly impaired in ß-xylosidase, transglucosidase, and transxylosidase activities, except for a slightly reduced xylosidase/glucosidase activity ratio of N370S GBA and a slightly reduced transglucosylation/glucosidase activity ratio of D409H GBA. XylChol was found to be reduced in spleen from patients with Gaucher disease. The origin of newly identified XylChol in mouse and human tissues was investigated. Cultured human cells exposed to exogenous ß-xylosides generated XylChol in a manner dependent on active lysosomal GBA but not the cytosol-facing ß-glucosidase GBA2. We later sought an endogenous ß-xyloside acting as donor in transxylosylation reactions, identifying xylosylated ceramide (XylCer) in cells and tissues that serve as donor in the formation of XylChol. UDP-glucosylceramide synthase (GCS) was unable to synthesize XylChol but could catalyze the formation of XylCer. Thus, food-derived ß-D-xyloside and XylCer are potential donors for the GBA-mediated formation of XylChol in cells. The enzyme GCS produces XylCer at a low rate. Our findings point to further catalytic versatility of GBA and prompt a systematic exploration of the distribution and role of xylosylated lipids.

15.
Front Mol Biosci ; 7: 177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005626

RESUMO

The brain is the physical organ of the mind but efforts to understand mental illness within a neurobiological context have hitherto been unavailing. Mental disorders (anxiety, depression, bipolar disorder, and schizophrenia) affect about one fifth of the population and present an almost endless societal challenge at the frontier of human sciences. Prodigious technological advances in functional neuroimaging and large-scale genetics have not yet delivered the prospect of refined molecular understanding of mental illness beyond early anatomical descriptions of brain metabolism. However, intensive clinical phenotyping and quantitative metabolic studies using sophisticated radio-ligands in positron-emission tomography, persistently favor the neurobiological approach. This Perspective pursues a familiar maxim in Medicine, aptly summarized in the words of Arthur Koestler: "Nature is generous in her senseless experiments on mankind." Hitherto, studies in neuropsychiatry have largely ignored rare genetic disorders but derangements of specific components within the cerebral laboratory offer rich opportunities for mechanistic exploration. Aberrant psychic behavior is characteristic of many inborn errors of metabolism and although each disorder represents a universe of its own, we are at a threshold for understanding, since contemporary genetics and cell biology furnish abundant materials to take on the perturbing enigma of mental derangement. A further development relates to orphan drugs with actions on defined molecular targets: these represent new ways to study the pathogenesis of psychiatric phenomena associated with rare diseases and in a manner not formerly possible. Here we introduce the frontier of schizophrenia and its strong association with late-onset Tay-Sachs disease as a paradigm to explore.

16.
Brain Commun ; 2(1): fcaa041, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32954297

RESUMO

Plasma amyloid-ß peptide concentration has recently been shown to have high accuracy to predict amyloid-ß plaque burden in the brain. These amyloid-ß plasma markers will allow wider screening of the population and simplify and reduce screening costs for therapeutic trials in Alzheimer's disease. The aim of this study was to determine how longitudinal changes in blood amyloid-ß track with changes in brain amyloid-ß. Australian Imaging, Biomarker and Lifestyle study participants with a minimum of two assessments were evaluated (111 cognitively normal, 7 mild cognitively impaired, 15 participants with Alzheimer's disease). Amyloid-ß burden in the brain was evaluated through PET and was expressed in Centiloids. Total protein amyloid-ß 42/40 plasma ratios were determined using ABtest® assays. We applied our method for obtaining natural history trajectories from short term data to measures of total protein amyloid-ß 42/40 plasma ratios and PET amyloid-ß. The natural history trajectory of total protein amyloid-ß 42/40 plasma ratios appears to approximately mirror that of PET amyloid-ß, with both spanning decades. Rates of change of 7.9% and 8.8%, were observed for total protein amyloid-ß 42/40 plasma ratios and PET amyloid-ß, respectively. The trajectory of plasma amyloid-ß preceded that of brain amyloid-ß by a median value of 6 years (significant at 88% confidence interval). These findings, showing the tight association between changes in plasma and brain amyloid-ß, support the use of plasma total protein amyloid-ß 42/40 plasma ratios as a surrogate marker of brain amyloid-ß. Also, that plasma total protein amyloid-ß 42/40 plasma ratios has potential utility in monitoring trial participants, and as an outcome measure.

17.
Front Physiol ; 11: 783, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754047

RESUMO

Variations in craniofacial morphology may arise as a result of adaptation to different environmental factors such as soft diet (SD), which lessens functional masticatory load. Prior studies have shown that changes in the masticatory muscle function associated with a switch to short-term SD led to changes in craniofacial morphology and alveolar bone architecture. However, the long-term effects of SD and the associated adaptive changes in craniofacial shape are unclear. Our novel study set out to profile prospective skull changes in mice fed with SDs over multiple generations using three-dimensional (3D) geometric morphometric analysis (GMA). Our results revealed that short-term SD consumption led to a significant decrease in craniofacial size, along with numerous shape changes. Long-term SD consumption over 15 continuous generations was not associated with changes in craniofacial size; however, shape analysis revealed mice with shortened crania and mandibles in the anteroposterior dimension, as well as relative widening in the transverse dimension compared to the average shape of all mice analyzed in our study. Moreover, changes in shape and size associated with different functional loads appeared to be independent - shape changes persisted after diets were switched for one generation, whereas size decreased after one generation and then returned to baseline size. Our study is the first to study the role of prolonged, multi-generational SD consumption in the determination of craniofacial size and shape.

18.
Genes (Basel) ; 11(8)2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32784565

RESUMO

Missense, nonsense, splice site and regulatory region variants in interferon regulatory factor 6 (IRF6) have been shown to contribute to both syndromic and non-syndromic forms of cleft lip and/or palate (CL/P). We report the diagnostic evaluation of a complex multigeneration family of Honduran ancestry with a pedigree structure consistent with autosomal-dominant inheritance with both incomplete penetrance and variable expressivity. The proband's grandmother bore children with two partners and CL/P segregates on both sides of each lineage. Through whole-exome sequencing of five members of the family, we identified a single shared synonymous variant, located in the middle of exon 7 of IRF6 (p.Ser307Ser; g.209963979 G>A; c.921C>T). The variant was shown to segregate in the seven affected individuals and through three unaffected obligate carriers, spanning both sides of this pedigree. This variant is very rare, only being found in three (all of Latino ancestry) of 251,352 alleles in the gnomAD database. While the variant did not create a splice acceptor/donor site, in silico analysis predicted it to impact an exonic splice silencer element and the binding of major splice regulatory factors. In vitro splice assays supported this by revealing multiple abnormal splicing events, estimated to impact >60% of allelic transcripts. Sequencing of the alternate splice products demonstrated the unmasking of a cryptic splice site six nucleotides 5' of the variant, as well as variable utilization of cryptic splice sites in intron 6. The ectopic expression of different splice regulatory proteins altered the proportion of abnormal splicing events seen in the splice assay, although the alteration was dependent on the splice factor. Importantly, each alternatively spliced mRNA is predicted to result in a frame shift and prematurely truncated IRF6 protein. This is the first study to identify a synonymous variant as a likely cause of NS-CL/P and highlights the care that should be taken by laboratories when considering and interpreting variants.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Fatores Reguladores de Interferon/genética , Mutação , Processamento Alternativo , Animais , Células COS , Chlorocebus aethiops , Fissura Palatina/patologia , Feminino , Fatores Reguladores de Interferon/metabolismo , Masculino , Linhagem , Sítios de Splice de RNA/genética
19.
Am J Med Genet A ; 182(7): 1555-1561, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32352199

RESUMO

The Society for Craniofacial Genetics and Developmental Biology (SCGDB) 42nd Annual Meeting was held at the MD Anderson Cancer Center in Houston, Texas from October 14-15, 2019. The SCGDB meeting included scientific sessions on the molecular regulation of craniofacial development, cell biology of craniofacial development, signaling during craniofacial development, translational craniofacial biology, and for the first time, a career development workshop. Over a one hundred attendees from 21 states, and representing over 50 different scientific institutions, participated. The diverse group of scientists included cell and developmental biologists and clinical geneticists, promoting excellent discussions about molecular pathways guiding abnormal cell behaviors and the resultant morphological changes to craniofacial development. The results were high-quality science and a welcoming environment for trainees interested in craniofacial biology.


Assuntos
Anormalidades Craniofaciais/genética , Biologia do Desenvolvimento , Animais , Distinções e Prêmios , Escolha da Profissão , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Crista Neural/patologia , Crista Neural/fisiologia , Sociedades Científicas , Xenopus/genética , Xenopus/crescimento & desenvolvimento
20.
Bone ; 137: 115408, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32407962

RESUMO

Whether in a clinical setting or a research environment using model organisms, X-ray-based computed tomography (CT) in its different forms represents the gold standard technology for the non-invasive imaging and quantification of mineralized tissues. While there are many excellent reviews on computed tomography in bone imaging, most focus on the appendicular skeleton. However, the craniofacial skeleton and mineralized dentition, which are frequently imaged for a variety of reasons, can require special considerations to ensure the best quality data are acquired and interpreted correctly. In this review, I will specifically focus on micro-computed tomography (microCT) related to the study of the craniofacial skeleton from the onset of cranioskeletal development through to adulthood using the mouse as the primary reference organism. In so doing, I will cover the important considerations when planning imaging studies, explain critical parameters of both scanning, reconstruction and 3D rendering of data that can impact quantification of different mineralized craniofacial tissues, and options for enabling accurate visualization of tomographic data.


Assuntos
Osso e Ossos , Imageamento Tridimensional , Animais , Camundongos , Microtomografia por Raio-X
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...