Decidual, amniotic fluid, maternal and fetal prolactin in normal and abnormal pregnancies.

Journal ArticleIn the present studies, the content and the in vitro production of prolactin by decidua as well as the concentrations of prolactin in amniotic fluid, maternal and fetal serum in normal term pregnancies, induced abortions at various gestational ages, and in pregnancies complicated by diabetes mellitus, preeclampsia, chronic hypertension, and polyhydramnios were measured. Maternal and fetal prolactin levels varied considerably throughout gestation, but at term did not differ significantly between normal and abnormal pregnancies. Prolactin levels in amniotic fluid as well as decidual prolactin content and production were significantly lower only in pregnancies complicated by either hypertension or polyhydramnios. In both normal and abnormal pregnancies, decidual prolactin production correlated strongly with amniotic fluid concentrations. The present data suggest that 1) maternal and fetal prolactin levels do not differ significantly between normal and abnormal pregnancies, 2) the decidua is the principal source of amniotic fluid prolactin, and 3) the significantly lower levels of prolactin in amniotic fluid of pregnancies complicated by hypertension or polyhydramnios are probably due to adverse effects of these conditions on the synthesis and release of prolactin by decidua

The economic impacts to commercial farms from invasive monkeys in Puerto Rico

Beginning in the 1930s and continuing through the 1970s, rhesus macaques and patas monkeys were introduced to presumed secure locations, primarily coastal islets, in Puerto Rico. Escapes into the wild began almost immediately after introduction. Today the combined range of the two species covers approximately 600 km2 of southwestern Puerto Rico, where serious conflicts with agricultural interests have resulted. The Puerto Rico Department of Agriculture surveyed about 90% of commercial farmers in the range of the monkeys to begin quantifying damage by monkeys and the associated economic losses during the years 2002–2006. During that time, total economic losses by commercial farmers to monkeys increased from $1.13 million USD to over$1.46 million per year. Of these amounts, the economic losses due to farmers avoiding monkey damage by switching from fruit and vegetable crops to less rewarding land use (primarily hay or pastureland) increased from $490,000 to$1.33 million per year. The losses reported from the survey represent only a portion of economic losses to the invasive monkeys. Subsistence and other smaller farms and agriculture were not included in the survey. We also discuss many other economic issues surrounding the impacts of the invasive monkeys, but for which sufficient data are not available for economic analyses. These include concerns such as destruction of native (especially endangered) wildlife, threat of disease spread, and property damage, all of which would also have to be considered to fully evaluate invasive monkey economic impacts in Puerto Rico

Aggregation and Representation in the European Parliament Party Groups

While members of the European Parliament are elected in national constituencies, their votes are determined by the aggregation of MEPs in multinational party groups. The uncoordinated aggregation of national party programmes in multinational EP party groups challenges theories of representation based on national parties and parliaments. This article provides a theoretical means of understanding representation by linking the aggregation of dozens of national party programmes in different EP party groups to the aggregation of groups to produce the parliamentary majority needed to enact policies. Drawing on an original data source of national party programmes, the EU Profiler, the article shows that the EP majorities created by aggregating MEP votes in party groups are best explained by cartel theories. These give priority to strengthening the EP’s collective capacity to enact policies rather than voting in accord with the programmes they were nationally elected to represent

Diferencia de presentación del síndrome coronario agudo por género en pacientes llevados al laboratorio de cateterismo en población dominicana: un estudio retrospectivo

Introducción: el síndrome coronario agudo (SCA) es una serie de signos y síntomas que se refieren a isquemia miocárdica repentina. Estas condiciones clínicas son Síndrome Coronario agudo sin Elevación del Segmento ST (SCASEST) y Síndrome Coronario Agudo con Elevación del Segmento ST (SCACEST). A nivel mundial hay hallazgos controversiales con respecto a la diferencia de presentación de SCA en hombres y mujeres. Objetivo: determinar las diferencias en presentación del síndrome coronario agudo según el género en República Dominicana. Métodos: en este estudio observacional retrospectivo unicéntrico, 3,548 pacientes con SCA llevados al laboratorio de cateterismo fueron observados durante el período de agosto de 2016 a septiembre de 2019. Resultados: la edad promedio de presentación fue mayor en las mujeres, con una media de 63 años (DE ± 12.2). El SCACEST fue más frecuente en hombres (69.35 %) y la Angina Inestable en mujeres (50.14 %, p <0.0001). Angiográficamente, la enfermedad coronaria multivascular fue más común en hombres y la angiografía coronaria normal en mujeres (41.30 % y 35.37 %, p <0.0001). Conclusión: dentro de la población dominicana, la mujer tiende a ser mayor al momento de presentación de SCA, con menor tendencia a someterse a intervención coronaria terapéutica

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome

Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.

Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance

Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice

AbstractDevelopmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS), NIH (R01NS109858, to VAG); the Paul A. Marks Scholar Program at the Columbia University Vagelos College of Physicians and Surgeons (to VAG); a TIGER grant from the TAUB Institute at the Columbia Vagelos College of Physicians and Scientists (to VAG); the Swiss National Science Foundation (SNF 31003A-179371, to TH); the European Joint Program on Rare Diseases (EJP RD+SNF 32ER30-187505, to TH); the Swiss Cancer League (KFS-4999-02-2020, to GD); the EPFL institutional fund (to GD); the Kristian Gerhard Jebsen Foundation (to GD); the Swiss National Science Foundation (SNSF) (310030_184926, to GD); the Swiss Foundation for Research on Muscle Disease (FSRMM, to MAL); the Natural Science and Engineering Research Council of Canada (Discovery Grant 2020-04241, to JEB); the Italian Ministry of Health Young Investigator Grant (GR-2011-02347754, to EL); the Fondazione Istituto di Ricerca Pediatrica – Città della Speranza (18-04, to EL); the Wroclaw Medical University (SUB.E160.21.004, to RS); the National Science Centre, Poland (2017/27/B/NZ5/0222, to RS); Telethon Undiagnosed Diseases Program (TUDP) (GSP15001); the Temple Street Foundation/Children’s Health Foundation Ireland (RPAC 19-02, to IK); the Deutsche Forschungsgemeinschaft (DFG) (PO2366/2–1, to BP); the Instituto de Salud Carlos III, Spain (to ELM, EBS, and BMD); the National Natural Science Foundation of China (81871079 and 81730036, to HG and KX); and the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH (R01 DK115574, to SSC).The DEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. The funders were not involved in the study design, data acquisition, analysis, or writing of the manuscript. Funding for the DECIPHER project was provided by Wellcome. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of Wellcome or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.S