Current Controversy on Platelets and Patent Ductus Arteriosus Closure in Preterm Infants.

Platelets are critically involved in murine patent ductus arteriosus (PDA) closure. To date, the clinical significance of these findings in human preterm infants with PDA is still controversial. We discuss the available study data on the role of platelets for PDA closure in preterm infants: Several mostly retrospective studies have yielded conflicting results on whether thrombocytopenia contributes to failed spontaneous ductal closure. The same applies to investigations on the role of thrombocytopenia as a risk factor for unsuccessful ductus arteriosus closure by pharmacological treatment with cyclooxygenase inhibitors. Nonetheless, recent meta-analyses have concluded that thrombocytopenia constitutes an independent risk factor for both failed spontaneous and pharmacological PDA closure in preterm infants. However, the available investigations differ in regard to patient characteristics, diagnostic strategies, and treatment protocols. Several studies suggest that impaired platelet function rather than platelet number is critically involved in failure of ductus arteriosus closure in the preterm infant. A recent randomized-controlled trial on platelet transfusions in preterm infants with PDA failed to show any benefit for liberal vs. restrictive transfusion thresholds on PDA closure rates. Importantly, liberal transfusions were associated with an increased rate of intraventricular hemorrhage, and thus should be avoided. In conclusion, the available evidence suggests that thrombocytopenia and platelet dysfunction contribute to failure of spontaneous and pharmacological PDA closure in preterm infants. However, these platelet effects on PDA seem to be of only moderate clinical significance. Furthermore, platelet transfusions in thrombocytopenic preterm infants in order to facilitate PDA closure appear to cause more harm than good

Workshop report: PlioWest – drilling Pliocene lakes in western North America

The Pliocene Epoch is a focus of scientific interest as a period of sustained global warmth, with reconstructed CO2 concentrations and a continent configuration similar to modern. Numerous studies suggest that the Pliocene was warmer and largely wetter than today, at least in the subtropics, which contrasts with the long-term hydroclimatic response of drying conditions predicted by most climate model simulations. Two key features of Pliocene warmth established from sea surface temperature reconstructions could affect dynamic changes that influence the hydrologic cycle: (1) a weaker Pliocene zonal gradient in sea surface temperature (SST) between the western and eastern equatorial Pacific resembling El Niño-like conditions and (2) polar-amplified Pliocene warmth, supporting a weaker Equator-to-pole temperature gradient. The distribution of wet conditions in western North America and the timing of late Pliocene–Quaternary aridification offer the potential to evaluate the relative roles of these two external forcings of the climate in western North America, with broader global implications for Mediterranean-type climate (MTC) regions. We convened a virtual ICDP workshop that spanned a 2-week period in September 2021, to choose optimal drill sites and legacy cores to address the overall scientific goals, flesh out research questions, and discuss how best to answer them. A total of 56 participants from 12 countries (17 time zones), representing a wide range of disciplines, came together virtually for a series of plenary and working group sessions. We have chosen to study five basins (Butte Valley, Tule Lake, Lake Idaho, Searles Lake, and Verde Valley) that span 7 ∘ of latitude to test our hypotheses and to reconstruct the evolution of western North American hydroclimate with special focus on the time ranges of 4.5–3.5 and 3–2.5 Myr. Although individual Pliocene lake records occur in many areas of the world, the western North American basins are unique and globally significant as deep perennial freshwater Pliocene lakes latitudinally arrayed in a MTC region and are able to capture a response to Pacific forcing. We propose new drill cores from three of these basins. During the workshop, we discussed the stratigraphy and subsurface structure of each basin and revised the chronological frameworks and the basin-to-basin correlations. We also identified the best-suited proxies for hydroclimate reconstructions for each particular basin and put forward a multi-technique strategy for depth–age modeling. Reconstructions based on data from these sites will complement the SST reconstructions from global sites spanning the last 4.5 Ma and elucidate the large-scale hydrological cycle controls associated with both global warming and cooling

Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma

Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer. Combined genomic and transcriptomic approaches identify the landscape of extrachromosomal circular DNA in neuroblastoma and reveal that extrachromosomal circular DNA is a major source of somatic rearrangements