How have advances in genetic technology modified movement disorder nosology?

The role of genetics and its technological development have been fundamental in advancing the field of movement disorders, opening the door to precision medicine. Starting from the revolutionary discovery of the locus of the Huntington’s disease gene, we review the milestones of genetic discoveries in movement disorders and their impact on clinical practice and research efforts. Before the 1980s, early techniques did not allow the identification of genetic alteration in complex diseases. Further advances increasingly defined a large number of pathogenic genetic alterations. Moreover, these techniques allowed epigenomic, transcriptomic and microbiome analyses. In the 2020s, these new technologies are poised to displace phenotype-based classifications towards a nosology based on genetic/biological data. Advances in genetic technologies are engineering a reversal of the phenotype-to-genotype order of nosology development, replacing convergent clinicopathological disease models with the genotypic divergence required for future precision medicine applications.Fil: Sturchio, A.. University of Cincinnati; Estados UnidosFil: Marsili, L.. University of Cincinnati; Estados UnidosFil: Mahajan, A.. University of Cincinnati; Estados UnidosFil: Grimberg, M.B.. University of Cincinnati; Estados UnidosFil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Espay, A.J.. University of Cincinnati; Estados Unido

Extended Emission Line Gas in Radio Galaxies - PKS0349-27

PKS0349-27 is a classical FRII radio galaxy with an AGN host which has a spectacular, spiral-like structure in its extended emission line gas (EELG). We have measured the velocity field in this gas and find that it splits into 2 cloud groups separated by radial velocities which at some points approach 400 km/s Measurements of the diagnostic emission line ratios [OIII]5007/H-beta, [SII]6716+6731/H-alpha, and [NII]6583/H-alpha in these clouds show no evidence for the type of HII region emission associated with starburst activity in either velocity system. The measured emission line ratios are similar to those found in the nuclei of narrow-line radio galaxies, but the extended ionization/excitation cannot be produced by continuum emission from the active nucleus alone. We present arguments which suggest that the velocity disturbances seen in the EELG are most likely the result of a galaxy-galaxy collision or merger but cannot completely rule out the possibility that the gas has been disrupted by the passage of a radio jet.Comment: 12 pages, 3 fig pages, to appear in the Astrophys.

Transitions in wheat endosperm metabolism upon transcriptional induction of oil accumulation by oat endosperm WRINKLED1

Background: Cereal grains, including wheat (Triticum aestivum L.), are major sources of food and feed, with wheat being dominant in temperate zones. These end uses exploit the storage reserves in the starchy endosperm of the grain, with starch being the major storage component in most cereal species. However, oats (Avena sativa L.) differs in that the starchy endosperm stores significant amounts of oil. Understanding the control of carbon allocation between groups of storage compounds, such as starch and oil, is therefore important for understanding the composition and hence end use quality of cereals. WRINKLED1 is a transcription factor known to induce triacylglycerol (TAG; oil) accumulation in several plant storage tissues. Results: An oat endosperm homolog of WRI1 (AsWRI1) expressed from the endosperm-specific HMW1Dx5 promoter resulted in drastic changes in carbon allocation in wheat grains, with reduced seed weight and a wrinkled seed phenotype. The starch content of mature grain endosperms of AsWRI1-wheat was reduced compared to controls (from 62 to 22% by dry weight (dw)), TAG was increased by up to nine-fold (from 0.7 to 6.4% oil by dw) and sucrose from 1.5 to 10% by dw. Expression of AsWRI1 in wheat grains also resulted in multiple layers of elongated peripheral aleurone cells. RNA-sequencing, lipid analyses, and pulse-chase experiments using 14C-sucrose indicated that futile cycling of fatty acids could be a limitation for oil accumulation. Conclusions: Our data show that expression of oat endosperm WRI1 in the wheat endosperm results in changes in metabolism which could underpin the application of biotechnology to manipulate grain composition. In particular, the striking effect on starch synthesis in the wheat endosperm indicates that an important indirect role of WRI1 is to divert carbon allocation away from starch biosynthesis in plant storage tissues that accumulate oil

Growth hormone deficiency in megalencephaly-capillary malformation syndrome: An association with activating mutations in PIK3CA

Megalencephaly-capillary malformation syndrome (MCAP) is a brain overgrowth disorder characterized by cortical malformations (specifically polymicrogyria), vascular anomalies, and segmental overgrowth secondary to somatic activating mutations in the PI3K-AKT-MTOR pathway (PIK3CA). Cases of growth failure and hypoglycemia have been reported in patients with MCAP, raising the suspicion for unappreciated growth hormone (GH) deficiency. Here we report an observational multicenter study of children with MCAP and GH deficiency. Eleven participants were confirmed to have GH deficiency, all with very low or undetectable circulating concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Seven underwent GH stimulation testing and all had insufficient responses with a median GH peak of 3.7 ng/ml (range 1.1-8.6). Growth patterns revealed a drastic decline in length z-scores within the first year of life but then stabilized afterward. Five were treated with GH; one discontinued due to inconsolability. The other four participants continued on GH with improvement in linear growth velocity. Other endocrinopathies were identified in 7 of the 11 participants in this cohort. This study indicates that GH deficiency is associated with MCAP and that children with MCAP and hypoglycemia and/or postnatal growth failure should be evaluated for GH deficiency and other endocrinopathies

Oportunidades perdidas na prevenção da sífilis congênita e da transmissão vertical do HIV

OBJECTIVE: To estimate the prevalence of missed opportunities for congenital syphilis and HIV prevention in pregnant women who had access to prenatal care and to assess factors associated to non-testing of these infections. METHODS: Cross-sectional study comprising a randomly selected sample of 2,145 puerperal women who were admitted in maternity hospitals for delivery or curettage and had attended at least one prenatal care visit, in Brazil between 1999 and 2000. No syphilis and/or anti-HIV testing during pregnancy was a marker for missed prevention opportunity. Women who were not tested for either or both were compared to those who had at least one syphilis and one anti-HIV testing performed during pregnancy (reference category). The prevalence of missed prevention opportunity was estimated for each category with 95% confidence intervals. Factors independently associated with missed prevention opportunity were assessed through multinomial logistic regression. RESULTS: The prevalence of missed prevention opportunity for syphilis or anti-HIV was 41.2% and 56.0%, respectively. The multivariate analysis showed that race/skin color (non-white), schooling (OBJETIVO: Estimar la prevalencia de oportunidad de pérdida de prevención de la sífilis y el HIV entre gestantes que tuvieron acceso al pre-natal y factores asociados con la no evaluación de estos agravios. MÉTODOS: Se realizó estudio transversal con muestra aleatoria de 2.145 puérperas de Brasil, 1999 y 2000 admitidas en maternidades para parto o curetaje y que habían realizado al menos una consulta de pre-natal. La no realización del examen de prueba para sífilis y/o anti-HIV durante el embarazo fue usada como marcador para oportunidad de pérdida de prevención. Las mujeres que realizaron sólo examen de sífilis o sólo examen de anti-HIV, o que no realizaron ninguno, fueron comparadas con las que realizaron los dos (categoría de referencia). La prevalencia de oportunidad de pérdida de prevención fue estimada para cada categoría, con intervalo de confianza de 95%. Los factores asociados con la oportunidad de pérdida de prevención fueron analizados por medio de regresión logística multinomial. RESULTADOS: La prevalencia de oportunidad de pérdida de prevención para la realización de la prueba de sífilis o anti-HIV fue de 41,2% e 56,0%, respectivamente. El análisis multivariado indicó que raza/color (no blanca), escolaridad (< 8 años de estudio), estado civil (soltera), renta < 3 salarios mínimos, relación sexual durante el embarazo, no haber tenido sífilis anterior al embarazo actual, realización de seis o mas consultas de pre-natal y la realización de la última visita antes del tercer trimestre de embarazo, estaban asociados con mayor riesgo de tener oportunidad de pérdida de prevención. Se observó una asociación negativa entre estado civil (soltera), lugar de realización de pre-natal (hospital) y la realización de la primera consulta pre-natal en el tercer trimestre con oportunidad de pérdida de prevención. CONCLUSIONES: Altos porcentajes de gestantes no evaluadas señalan fallas en la prevención y control de la infección por HIV y de la sífilis congénita en los servicios de salud. Las gestantes continúan interrumpiendo el cuidado pre-natal precozmente y no logran realizar los procedimientos de selección para HIV y sífilis.OBJETIVO: Estimar a prevalência de oportunidade perdida de prevenção a sífilis e HIV entre gestantes que tiveram acesso ao pré-natal e fatores associados a não-testagem para esses agravos. MÉTODOS: Estudo transversal com amostra aleatória de 2.145 puérperas do Brasil, 1999 e 2000 admitidas em maternidades para parto ou curetagem e que haviam realizado pelo menos uma consulta de pré-natal. A não-realização de exame de teste para sífilis e/ou anti-HIV durante a gravidez foi usada como marcador para oportunidade perdida de prevenção. Mulheres que realizaram apenas exame de sífilis ou apenas o anti-HIV, ou não realizaram nenhum, foram comparadas àquelas que realizaram os dois (categoria de referência). A prevalência de oportunidade perdida de prevenção foi estimada para cada categoria, com intervalo de confiança de 95%. Os fatores associados com oportunidade perdida de prevenção foram analisados por meio de regressão logística multinomial. RESULTADOS: A prevalência de oportunidade perdida de prevenção para a realização do teste de sífilis ou anti-HIV foi de 41,2% e 56,0%, respectivamente. A análise multivariada indicou que raça/cor (não branca), escolaridade (< 8 anos de estudo), estado civil (solteira), rend

Global gene expression patterns in the post-pneumonectomy lung of adult mice

<p>Abstract</p> <p>Background</p> <p>Adult mice have a remarkable capacity to regenerate functional alveoli following either lung resection or injury that exceeds the regenerative capacity observed in larger adult mammals. The molecular basis for this unique capability in mice is largely unknown. We examined the transcriptomic responses to single lung pneumonectomy in adult mice in order to elucidate prospective molecular signaling mechanisms used in this species during lung regeneration.</p> <p>Methods</p> <p>Unilateral left pneumonectomy or sham thoracotomy was performed under general anesthesia (n = 8 mice per group for each of the four time points). Total RNA was isolated from the remaining lung tissue at four time points post-surgery (6 hours, 1 day, 3 days, 7 days) and analyzed using microarray technology.</p> <p>Results</p> <p>The observed transcriptomic patterns revealed mesenchymal cell signaling, including up-regulation of genes previously associated with activated fibroblasts (Tnfrsf12a, Tnc, Eln, Col3A1), as well as modulation of Igf1-mediated signaling. The data set also revealed early down-regulation of pro-inflammatory cytokine transcripts and up-regulation of genes involved in T cell development/function, but few similarities to transcriptomic patterns observed during embryonic or post-natal lung development. Immunohistochemical analysis suggests that early fibroblast but not myofibroblast proliferation is important during lung regeneration and may explain the preponderance of mesenchymal-associated genes that are over-expressed in this model. This again appears to differ from embryonic alveologenesis.</p> <p>Conclusion</p> <p>These data suggest that modulation of mesenchymal cell transcriptome patterns and proliferation of S100A4 positive mesenchymal cells, as well as modulation of pro-inflammatory transcriptome patterns, are important during post-pneumonectomy lung regeneration in adult mice.</p

Cross-species Malaria Immunity Induced By Chemically Attenuated Parasites

Vaccine development for the blood stages of malaria has focused on the induction of antibodies to parasite surface antigens, most of which are highly polymorphic. An alternate strategy has evolved from observations that low-density infections can induce antibody-independent immunity to different strains. To test this strategy, we treated parasitized red blood cells from the rodent parasite Plasmodium chabaudi with secocyclopropyl pyrrolo indole analogs. These drugs irreversibly alkylate parasite DNA, blocking their ability to replicate. After administration in mice, DNA from the vaccine could be detected in the blood for over 110 days and a single vaccination induced profound immunity to different malaria parasite species. Immunity was mediated by CD4(+) T cells and was dependent on the red blood cell membrane remaining intact. The human parasite, Plasmodium falciparum, could also be attenuated by treatment with seco-cyclopropyl pyrrolo indole analogs. These data demonstrate that vaccination with chemically attenuated parasites induces protective immunity and provide a compelling rationale for testing a blood-stage parasite-based vaccine targeting human Plasmodium species

Evaluation of three instrumentation techniques at the precision of apical stop and apical sealing of obturation

OBJECTIVE: The aim of this study was to investigate the ability of two NiTi rotary apical preparation techniques used with an electronic apex locator-integrated endodontic motor and a manual technique to create an apical stop at a predetermined level (0.5 mm short of the apical foramen) in teeth with disrupted apical constriction, and to evaluate microleakage following obturation in such prepared teeth. MATERIAL AND METHODS: 85 intact human mandibular permanent incisors with single root canal were accessed and the apical constriction was disrupted using a #25 K-file. The teeth were embedded in alginate and instrumented to #40 using rotary Lightspeed or S-Apex techniques or stainless-steel K-files. Distance between the apical foramen and the created apical stop was measured to an accuracy of 0.01 mm. In another set of instrumented teeth, root canals were obturated using gutta-percha and sealer, and leakage was tested at 1 week and 3 months using a fluid filtration device. RESULTS: All techniques performed slightly short of the predetermined level. Closest preparation to the predetermined level was with the manual technique and the farthest was with S-Apex. A significant difference was found between the performances of these two techniques (