A systematic catalog of studies on fetal heart rate pattern and neonatal outcome variables

To study the methodology and results of studies assessing the relationship between fetal heart rate and specified neonatal outcomes including, heart rate, infection, necrotizing enterocolitis, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, and seizure. Embase, Medline ALL, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and CINAHL were searched from inception to October 5, 2023. Forty-Two studies were included, encompassing 57,232 cases that underwent fetal monitoring and were evaluated for neonatal outcome. Heterogeneity was observed in the timing and duration of fetal heart rate assessment, classification guidelines used, number of assessors, and definition and timing of neonatal outcome assessment. Nonreassuring fetal heart rate was linked to lower neonatal heart rate variability. A significant increase in abnormal fetal heart rate patterns were reported in neonates with hypoxic-ischemic encephalopathy, but the predictive ability was found to be limited. Conflicting results were reported regarding sepsis, seizure and intraventricular hemorrhage. No association was found between necrotizing enterocolitis rate and fetal heart rate. There is great heterogeneity in the methodology used in studies evaluating the association between fetal heart rate and aforementioned neonatal outcomes. Hypoxic-ischemic encephalopathy was associated with increased abnormal fetal heart rate patterns, although the predictive ability was low. Further research on developing and evaluating an automated early warning system that integrates computerized cardiotocography with a perinatal health parameter database to provide objective alerts for patients at-risk is recommended.</p

Human Intelligence and Polymorphisms in the DNA Methyltransferase Genes Involved in Epigenetic Marking

Epigenetic mechanisms have been implicated in syndromes associated with mental impairment but little is known about the role of epigenetics in determining the normal variation in human intelligence. We measured polymorphisms in four DNA methyltransferases (DNMT1, DNMT3A, DNMT3B and DNMT3L) involved in epigenetic marking and related these to childhood and adult general intelligence in a population (n = 1542) consisting of two Scottish cohorts born in 1936 and residing in Lothian (n = 1075) or Aberdeen (n = 467). All subjects had taken the same test of intelligence at age 11yrs. The Lothian cohort took the test again at age 70yrs. The minor T allele of DNMT3L SNP 11330C>T (rs7354779) allele was associated with a higher standardised childhood intelligence score; greatest effect in the dominant analysis but also significant in the additive model (coefficient = 1.40additive; 95%CI 0.22,2.59; p = 0.020 and 1.99dominant; 95%CI 0.55,3.43; p = 0.007). The DNMT3L C allele was associated with an increased risk of being below average intelligence (OR 1.25additive; 95%CI 1.05,1.51; p = 0.011 and OR 1.37dominant; 95%CI 1.11,1.68; p = 0.003), and being in the lowest 40th (padditive = 0.009; pdominant = 0.002) and lowest 30th (padditive = 0.004; pdominant = 0.002) centiles for intelligence. After Bonferroni correction for the number variants tested the link between DNMT3L 11330C>T and childhood intelligence remained significant by linear regression and centile analysis; only the additive regression model was borderline significant. Adult intelligence was similarly linked to the DNMT3L variant but this analysis was limited by the numbers studied and nature of the test and the association was not significant after Bonferroni correction. We believe that the role of epigenetics in the normal variation in human intelligence merits further study and that this novel finding should be tested in other cohorts

A Novel High-Affinity Sucrose Transporter Is Required for Virulence of the Plant Pathogen Ustilago maydis

A novel, high-affinity sucrose transporter identified in the plasma membrane of the plant pathogen Ustilago maydis is essential for fungal virulence and successful infection of maize

Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

Purpose Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. Methods We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. Results We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. Conclusion Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping

Multiple Scenario Generation of Subsurface Models:Consistent Integration of Information from Geophysical and Geological Data throuh Combination of Probabilistic Inverse Problem Theory and Geostatistics

Neutrinos with energies above 1017 eV are detectable with the Surface Detector Array of the Pierre Auger Observatory. The identification is efficiently performed for neutrinos of all flavors interacting in the atmosphere at large zenith angles, as well as for Earth-skimming \u3c4 neutrinos with nearly tangential trajectories relative to the Earth. No neutrino candidates were found in 3c 14.7 years of data taken up to 31 August 2018. This leads to restrictive upper bounds on their flux. The 90% C.L. single-flavor limit to the diffuse flux of ultra-high-energy neutrinos with an E\u3bd-2 spectrum in the energy range 1.0 7 1017 eV -2.5 7 1019 eV is E2 dN\u3bd/dE\u3bd &lt; 4.4 7 10-9 GeV cm-2 s-1 sr-1, placing strong constraints on several models of neutrino production at EeV energies and on the properties of the sources of ultra-high-energy cosmic rays

Alien Registration- Goos, Sarah (Bangor, Penobscot County)

https://digitalmaine.com/alien_docs/16012/thumbnail.jp

Die Rolle von Snail und Slug in der Invasion und Krebsstammzell-Erhaltung in Gioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common tumour of the central nervous system. Despite some progress in the therapy of the disease, patients still have a poor prognosis and a median survival of approximately 15 months. The biggest obstacle for successful surgical removal of glioblastoma is the high infiltration of invasive cancer cells throughout the brain. This makes it impossible to remove the complete tumour tissue, eventually resulting in relapse. Recent evidence suggests that glial-to-mesenchymal transition (GMT), a cellular program comparable to epithelial-to-mesenchymal transition (EMT), could play a major role in controlling the invasiveness of glioma cells. The transcription factors Snail and Slug are known to be major regulators of EMT in epithelial cancers. We therefore hypothesized that they may act as key components of GMT in glioma. Analysis of the expression of Snail and Slug in GBMs of different molecular subclasses revealed that these two EMT regulators are mainly expressed in the mesenchymal GBM subclass. By profiling a panel of signature markers we demonstrate that the combined loss of Snail and Slug impaired the TGFß1-induced transition from a glial/proneural phenotype to a mesenchymal phenotype in GBM cells. Furthermore, we show that Snail and Slug play a crucial role in controlling glioblastoma stem cell properties, such as self-renewal and the expression of cancer stem cell markers. In line with their role in GMT, Snail and Slug silencing led to a severely impaired invasive behaviour of GBM cells in vitro. Importantly, we found that Snail and Slug silenced GBM cells showed significantly reduced tumour growth in an orthotopic mouse xenograft model. Detailed analysis revealed that the reduced growth did not result from changes in proliferation and apoptosis due to the silencing of Snail and Slug. Instead, the invasiveness of Snail and Slug silenced cells was drastically reduced. In summary, this work demonstrates that Snail and Slug are major regulators of GMT in glioma, controlling the transition from a glial/proneural to a mesenchymal phenotype. Importantly, the mesenchymal phenotype is closely connected to the adoption of invasive and stem cell properties indicating that these are the major mechanisms through which Snail and Slug regulate GBM growth. This improved understanding of GMT in glioma could help to optimize existing GBM treatments and provide a basis for the development of novel therapeutic strategies.Glioblastoma multiforme (GBM) ist der häufigste Tumor des zentralen Nervensystems. Trotz großer Fortschritte in der Therapie der Erkrankung haben Patienten immer noch eine schlechte Prognose und eine mittlere Lebenserwartung von 15 Monaten. Das größte Hindernis bei der chirurgischen Entfernung des Tumors ist die hohe Infiltration des Gehirns durch invasive Krebszellen. Dadurch ist es nahezu unmöglich das vollständige Tumorgewebe zu entfernen und viele Patienten leiden unter einem Rezidiv. Neueste Erkenntnisse legen nahe, dass gliale zu mesenchymale Transition (GMT), ein zelluläres Programm vergleichbar mit epithelialer zu mesenchymaler Transition (EMT), eine wichtige Rolle bei der Kontrolle der Invasivität von Gliomzellen spielt. Es ist bekannt, dass die Transkriptionsfaktoren Snail und Slug EMT-Hauptregulatoren in epithelialen Tumoren sind. Daher nehmen wir an, dass diese Transkriptionsfaktoren ebenfalls Schlüsselkomponenten von GMT in GBM sind. Eine Analyse der Expression von Snail und Slug in GBMs in verschiedenen molekularen Unterklassen zeigte, dass diese beiden Regulatoren vor allem in der mesenchymalen GBM-Unterklasse exprimiert werden. Wir zeigen anhand der Expression einiger Signaturmarker, dass der gleichzeitige Verlust von Snail und Slug den TGFß1-induzierten Übergang von einem glialen/proneuralen Phänotypen hin zu einem mesenchymalen Phänotypen verhindert. Darüber hinaus demonstrieren wir, dass Snail und Slug eine entscheidende Rolle bei der Kontrolle der Glioblastom-Stammzelleigenschaften wie Selbsterneuerung und der Expression von Krebsstammzellmarker spielen. Der Verlust von Snail und Slug führte des Weiteren zu einer starken Beeinträchtigung des invasiven Verhaltens der Krebszellen in vitro. Wichtig ist, dass reduzierte Snail und Slug Expression in GBM Zellen zu einem signifikant reduzierten Tumorwachstum in einem orthotopischen Maus-Xenograft-Modell führte. Detaillierte Analyse der Tumore zeigte, dass das reduzierte Wachstum nicht von Veränderungen der Proliferation und Apoptose der Zellen herrührte. Stattdessen konnten wir durch eine in vivo Invasionanalyse belegen, dass der Verlust von Snail und Slug die Invasionsfähigkeit der Zellen signifikant verringert. Zusammenfassend zeigt diese Arbeit, dass Snail und Slug wichtige GMTRegulatoren sind die den Übergang von einem glialen/proneuralen zu einem mesenchymalen Phänotypen kontrollieren. Wichtig ist, dass der mesenchymale Phänotyp sehr eng mit der Invasivität und dem Erwerb von Stammzell-Eigenschaften der Gliomzellen verknüpft ist. Das legt nahe, dass dies wichtige Mechanismen sind durch die Snail und Slug das Tumorwachstum von GBM kontrollieren. Dieses verbesserte Verständnis von GMT könnte dazu beitragen bestehende Behandlungsformen von GBM zu verbessern und neue therapeutische Ansätze zu finden

Alien Registration- Goos, Sarah (Bangor, Penobscot County)

https://digitalmaine.com/alien_docs/16012/thumbnail.jp