Exposure of organisms to low concentrations of pesticides can have cumulative sublethal effects, influencing energy metabolism, fitness and reproductive success, producing effects at the population level. To assess the impact of glyphosate and 2,4-D herbicides, as well as the insecticide imidacloprid, both individually and in combination, at environmentally relevant concentrations, the gills of adult zebrafish were used due to their intimate interaction with chemicals diluted in water. Bioassays were performed exposing the animals to the different pesticides and their mixture for 96 hours, with daily changes of solution. Histological examinations, genotoxic effect, behavioral analyses and expression profiling of genes related to oxidative stress and apoptosis pathways were conducted. A noteworthy observation was the highest locomotion (length traveled and average speed) exhibited by the control fish compared to the animals exposed to glyphosate, 2,4-D, imidacloprid and mostly to those exposed to the mixture. All the groups exposed to pesticides individually exhibited a decrease in thigmotaxis time, indicating a reduction in the behavior of protecting themselves from predators. The comet assay (CA) revealed the sensitivity of gill cells to DNA damage following exposure to glyphosate, 2,4-D, imidacloprid and the mixture. The histological analysis revealed significant disparities in tissue structures. Exposure to imidacloprid produced mild injury (G1), glyphosate produced moderate (G2) to severe (G3) injury, 2,4-D and the mixture generated severe lesions (G3). Finally, both genes involved in the oxidative stress pathway and those related to the cell apoptosis pathway were overexpressed, while the ogg1 gene, involved in DNA repair, was downregulated.
Neurodevelopmental disorders are the most common diagnosis in the clinical practice in child neurology. Since the 70's the terminology used for the diagnosis of these conditions, was developed with the goal of obtaining better services for those individuals affected. Over the years the classification has changed but the fundamental process for diagnosis continues the same. There is a new movement aiming to change the current classification and propose a new one based in the molecular deficits associated with the clinical phenotype rather than a collection of symptoms. This new approach focusses on the identification of the molecular defectcausing of the specific to design targeted interventions that will promise a curative approach, rather than the current symptom-based interventions available. Important progress has been done alrea dy, given the high association between cognitive/compartmental phenotype in some well-known genetic defects like Neurofibromatosis, TSC, Down syndrome, and the high association between different cognitive/compartmental phenotype in rare diseases. The future will hold opportunities to properly identify the molecular deficit and a tailored intervention for those conditions today called Neurodevelopmental disabilities.Los desórdenes del Neurodesarrollo son en conjunto los diagnósticos más frecuentes en la práctica clínica en Neurología Infantil. De los años 70', se desarrolló una terminología usada para denominar estos desordenes, con el objetivo de obtener mejor atención en servicios médicos y educativos para los afectados. A lo largo de los años, las clasificaciones han cambiado, pero el proceso fundamental del diagnóstico sigue siendo el mismo. Existe actualmente un movimiento para cambiar y establecer una nueva clasificación, basada en los déficits biológicos asociados con el fenotípico clínico. Esta nueva aproximación diagnóstica tiene como objetivo entre tantos otros, el diseño de intervenciones específicas que prometerían un mayor potencial curativo, a diferencia de las actuales opciones de tratamiento, que se basan en el manejo de síntomas. Importantes progresos se han hecho ya en este campo. Por ejemplo, algunos fenotipos conductuales en condiciones genéticas ampliamente conocidas como el Síndrome de Down, síndrome de X Frágil, neurofibromatosis, esclerosis tuberosa entre otros, han permitido proponer correlaciones biológicas con fenotipos comunes en pacientes con autismo, trastornos por déficit de atención, entre otros. Adicionalmente, el extenso estudio que actualmente se lleva a cabo sobre las denominadas enfermedades raras, que se asocian hasta en un 80% con trastornos del neurodesarrollo, ha abierto la posibilidad para muchas más correlaciones biológicas-comportamentales. En el futuro, será posible esperar oportunidades para la identificación de déficits biológicos moleculares, asociados con fenotipos clínicos cognitivos-conductuales y que, a partir de ellos se puedan diseñar intervenciones individuales a los problemas que hoy conocemos globalmente como los desórdenes del neurodesarrollo.
Low-grade gliomas represent the most frequent primary brain tumors in children, and are also an important category of brain neoplasms in young adults. They are characterized by slow growth, but often associated with increased morbidity, as well as mortality in the subset that develop histologic progression. Pathologically they correspond to WHO grade I or II and include pilocytic astrocytoma (PA), pilomyxoid astrocytoma variant, angiocentric glioma, diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, and pleomorphic xanthoastrocytoma (PXA). Although all low-grade glioma subtypes may develop in children and adults, and be histologically indistinguishable in these two populations, there are important clinical and molecular differences. As a rule, low-grade gliomas in adults have a greater tendency for histologic progression and more aggressive clinical behavior than those in children. With respect to genetic alterations, activating BRAF alterations and increased MAPK pathway signaling are near universal features of the circumscribed low-grade glioma group (e.g., PA and PXA). Whole exome/genome sequencing efforts and high resolution copy number platforms have also provided important biologic insights in these tumors, with adult low-grade diffuse gliomas containing frequent ATRX, TP53 mutations (astrocytomas), as well as 1p19q co-deletions, CIC, FUBP1 and TERT promoter mutations (oligodendrogliomas). Conversely, alterations in FGFR1, MYB, and MYBL1 are frequent events in pediatric low-grade diffuse gliomas. In this review we summarize our current knowledge of the diagnostic and molecular pathology of these tumors, and explore possible avenues for targeted therapeutics.
Abstract Background Short tandem repeats (STRs) are widely distributed across the human genome and are associated with numerous neurological disorders. However, the extent that STRs contribute to disease is likely under-estimated because of the challenges calling these variants in short read next generation sequencing data. Several computational tools have been developed for STR variant calling, but none fully address all of the complexities associated with this variant class. Results Here we introduce LUSTR which is designed to address some of the challenges associated with STR variant calling by enabling more flexibility in defining STR loci, allowing for customizable modules to tailor analyses, and expanding the capability to call somatic and multiallelic STR variants. LUSTR is a user-friendly and easily customizable tool for targeted or unbiased genome-wide STR variant screening that can use either predefined or novel genome builds. Using both simulated and real data sets, we demonstrated that LUSTR accurately infers germline and somatic STR expansions in individuals with and without diseases. Conclusions LUSTR offers a powerful and user-friendly approach that allows for the identification of STR variants and can facilitate more comprehensive studies evaluating the role of pathogenic STR variants across human diseases.
Genetic factors are strongly implicated in the susceptibility to develop externalizing syndromes such as attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, and substance use disorder (SUD). Variants in the ADGRL3 (LPHN3) gene predispose to ADHD and predict ADHD severity, disruptive behaviors comorbidity, long-term outcome, and response to treatment. In this study, we investigated whether variants within ADGRL3 are associated with SUD, a disorder that is frequently co-morbid with ADHD. Using family-based, case-control, and longitudinal samples from disparate regions of the world (n = 2698), recruited either for clinical, genetic epidemiological or pharmacogenomic studies of ADHD, we assembled recursive-partitioning frameworks (classification tree analyses) with clinical, demographic, and ADGRL3 genetic information to predict SUD susceptibility. Our results indicate that SUD can be efficiently and robustly predicted in ADHD participants. The genetic models used remained highly efficient in predicting SUD in a large sample of individuals with severe SUD from a psychiatric institution that were not ascertained on the basis of ADHD diagnosis, thus identifying ADGRL3 as a risk gene for SUD. Recursive-partitioning analyses revealed that rs4860437 was the predominant predictive variant. This new methodological approach offers novel insights into higher order predictive interactions and offers a unique opportunity for translational application in the clinical assessment of patients at high risk for SUD.
Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants.DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
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