The Endothelial Protein C Receptor enhances FVIIa mediated hemostasis

Recombinant activated human Factor VII (rFVIIa) is an established hemostatic agent in hemophilia but its mechanism of action remains unclear. Although tissue factor (TF) is its natural receptor, rFVIIa also interacts with the endothelial protein C receptor (EPCR) through its g-carboxyglutamic acid (Gla) domain with unknown hemostatic consequences in vivo. Here, we study whether EPCR facilitates rFVIIa hemostasis in hemophilia using a mouse model system. Murine activated FVII (mFVIIa) is functionally homologous to rFVIIa, but binds poorly to murine EPCR (mEPCR). We modified mFVIIa to gain mEPCR binding using 3 amino acid changes in its Gla-domain. The resulting molecule mFVIIa-FMR specifically bound mEPCR in vitro and in vivo and was identical to mFVIIa with respect to TF affinity and procoagulant functions. Using two macrovascular injury models in hemophilic mice, administered mFVIIa-FMR exhibited superior hemostatic properties compared to mFVIIa. These effects were specific to the mFVIIa- FMR and mEPCR interaction since antibody blocking of mEPCR abolished them. Since mFVIIa-FMR models both the TF-dependent as well as EPCR binding properties of rFVIIa, our data unmask a novel contribution of EPCR on the action of rFVIIa administration in hemophilia. This may prompt the rational design of improved and safer rFVIIa therapeutics

Testing alternative hypotheses for the decline of cichlid fish in Lake Victoria using fish tooth time series from sediment cores.

Lake Victoria is well known for its high diversity of endemic fish species and provides livelihoods for millions of people. The lake garnered widespread attention during the twentieth century as major environmental and ecological changes modified the fish community with the extinction of approximately 40% of endemic cichlid species by the 1980s. Suggested causal factors include anthropogenic eutrophication, fishing, and introduced non-native species but their relative importance remains unresolved, partly because monitoring data started in the 1970s when changes were already underway. Here, for the first time, we reconstruct two time series, covering the last approximately 200 years, of fish assemblage using fish teeth preserved in lake sediments. Two sediment cores from the Mwanza Gulf of Lake Victoria, were subsampled continuously at an intra-decadal resolution, and teeth were identified to major taxa: Cyprinoidea, Haplochromini, Mochokidae and Oreochromini. None of the fossils could be confidently assigned to non-native Nile perch. Our data show significant decreases in haplochromine and oreochromine cichlid fish abundances that began long before the arrival of Nile perch. Cyprinoids, on the other hand, have generally been increasing. Our study is the first to reconstruct a time series of any fish assemblage in Lake Victoria extending deeper back in time than the past 50 years, helping shed light on the processes underlying Lake Victoria's biodiversity loss

Long-term ecological successions of vegetation around Lake Victoria (East Africa) in response to latest Pleistocene and Early Holocene climatic changes

Reconstructions of ecosystem dynamics in tropical East Africa during the latest Pleistocene and the Holocene provide important long-term ecological insights, but so far, only a few, sometimes incomplete terrestrial records exist. In this paper, we present a new high-resolution palynological record from the Lake Victoria basin, covering the period from 16,600 to 9000 cal yr BP, when Afromontane forests and tropical rainforests gradually replaced the savanna. We discuss this dataset in the context of published palaeoclimate data, TEX86 inferred temperature and δD leaf wax inferred precipitation records, to assess long-term ecological successions and their potential causes. By ca. 16,500 cal yr BP, the movement of the Afrotropical rainbelt, not only brought an increase in temperature and moisture into the Lake Victoria basin, but also promoted the spread of arboreal taxa, such as Celtis and Podocarpus, at the expense of the savanna. At that time, fires were prominent in the sparse Afromontane vegetation. Later from ca. 15,500–15,000 cal yr BP, temperature and humidity rose and Afromontane trees such as Olea and Macaranga spread slightly, while grasses were burning in the savanna. During the period from 13,250 to 10,700 cal yr BP, Afromontane vegetation dominated by Olea became more prominent and expanded towards the lowlands where the tropical rainforest or gallery forest established; however, the savanna only marginally retreated. An initial spread of tropical rainforests occurred from ca. 11,500–11,100 cal yr BP during the onset of the Holocene, when temperatures and moisture further increased. Subsequently, between 10,700 and 10,300 cal yr BP the tropical savanna was largely replaced by the tropical rainforest, while the Afromontane forest likely spread to higher elevations, similar to the patterns observed today. Our high-resolution record demonstrates the dynamic response of African tropical ecosystems to major temperature and humidity variations from 16,600 to 9000 cal yr BP, including some of the most important landscape transformations in East Africa in the past 20,000 years

Targeted Gene Delivery: Where to Land

International audienceGenome-editing technologies have the potential to correct most genetic defects involved in blood disorders. In contrast to mutation-specific editing, targeted gene insertion can correct most of the mutations affecting the same gene with a single therapeutic strategy (gene replacement) or provide novel functions to edited cells (gene addition). Targeting a selected genomic harbor can reduce insertional mutagenesis risk, while enabling the exploitation of endogenous promoters, or selected chromatin contexts, to achieve specific transgene expression levels/patterns and the modulation of disease-modifier genes. In this review, we will discuss targeted gene insertion and the advantages and limitations of different genomic harbors currently under investigation for various gene therapy applications

Author Correction: Ex vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Latest pleistocene and holocene primary producer communities and hydroclimate in Lake Victoria, Eastern Africa

The Lake Victoria ecosystem is emblematic of the catastrophic effects that human activities, particularly cultural eutrophication, can have on freshwater biodiversity. However, little is known about the long-term spatial and temporal pattern of aquatic primary paleo-production (PPaq) and producer communities in Lake Victoria and how these patterns relate to past climate variability, landscape evolution, lake hydrology, mixing regimes, nutrient cycling, and biodiversity dynamics in the past 17 kyr. We use sediments from four well-dated cores along a transect from offshore to nearshore sites, and exploit XRF element scanning and hyperspectral imaging data, TC, TN, bSi, δ13C and δ15N, and sedimentary pigments to investigate paleolimnological variability and change. Our findings demonstrate that changes in PPaq and algal communities during the past 17 kyr were closely related to hydroclimatic changes, lake mixing, and nutrient availability. During the wetland phase (16.7–14.5 cal ka BP), PPaq levels remained generally low, while chromophytes and chlorophytes dominated the algal community. Following the rapid lake level rise (∼14.2 cal ka BP) during the early African Humid Period (AHP), PPaq levels steadily increased, accompanied by a shift towards cyanobacteria and chromophytes. During the Holocene, our results suggest repeated short-lived arid intervals (∼10.5, ∼9, 7.8–7.2, ∼4, and 3.2–3.0 cal ka BP) and two distinct periods of enhanced lake mixing associated with high PPaq and high diatom productivity: the first one between 11 and 9 cal ka BP, which coincided with the maximum of the AHP (high precipitation, high wind, enhanced mixing), and the second, less pronounced one, between 7 and 4 cal ka BP. Between these two periods (i.e. 9–7 cal ka BP) we observe reduced diatom productivity, relatively low PPaq, and high C/N ratios, suggesting conditions with more stable lake stratification, likely associated with reduced wind strength, and some nutrient limitation (N and P). Finally, the drier conditions around the end of the AHP (ca. 4 cal ka BP) and during the late Holocene were associated with decreasing lake mixing and increasing dominance of cyanobacteria. Given our reconstruction of PPaq over the past 17 kyr, we conclude that the levels in the 20th century are unprecedentedly high, consistent with the massive human-mediated impact on the Lake Victoria ecosystem including biodiversity loss

Clinical Outcomes of Percutaneous Left-Atrial Appendage Occlusion with Conscious Sedation without an Anesthesiologist on Site: Results from a Multicenter Study

Background and Objectives: Percutaneous left-atrial appendage (LAA) occlusion is an important therapeutic option for preventing cardioembolic stroke in patients with non-valvular atrial fibrillation (AF) at high risk of thromboembolic events and with contraindications for oral anticoagulation (OAC). It is usually performed with transesophageal echocardiography (TOE) guidance under general anesthesia (GA). In this retrospective study, we present a multicenter experience of LAA occlusion performed with conscious sedation (CS) without an anesthesiologist on site. Materials and Methods: All the patients on the waiting list for LAA occlusion procedure at Infermi Hospital, Rivoli, and San Luigi Gonzaga University Hospital, Orbassano, from October 2018 to October 2022 were analyzed. All the procedures were performed with a Watchman/FLX LAA closure device under TOE and fluoroscopic guidance without an anesthesiologist on site. CS was performed with a combination of midazolam and fentanyl as needed. Results: One-hundred fifteen patients were included (age 76.4 ± 7.6 years, median CHA2DS2Vasc 4.4 ± 1.4). CS was performed using midazolam (mean dose 5.9 ± 2.1 mg), adding fentanyl for thirty-nine (33.9%) patients in case of poor tolerance for the procedure despite midazolam. The acute procedural success rate was 99.1%. We observed seven acute severe complications. No patients needed anesthesiological assistance during the procedure, and no cases of respiratory failure necessitating ventilation were reported. In a follow-up after 10 ± 9 months, one case of stroke (0.9%) and one case (0.9%) of transient ischemic attack (TIA) occurred. Conclusions: LAA occlusion performed under CS and without the presence of an anesthesiologist on site appears to be safe and effective. It can be an attractive alternative to general anesthesia (GA), as fewer resources are required