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Reversing factor Xa inhibitors - clinical utility of andexanet alfa

Approximately half of patients started on an oral anticoagulant in the USA now receive one of the newer direct oral anticoagulants (DOACs). Although there is an approved reversal agent for the direct thrombin inhibitor dabigatran, a specific reversal agent for the anti-factor Xa (FXa) DOACs has yet to be licensed. Unlike the strategy to reverse the only oral direct thrombin inhibitor with idarucizumab, which is a humanized monoclonal antibody fragment, a different approach is necessary to design a single agent that can reverse multiple anti-FXa medications. Andexanet alfa is a FXa decoy designed to reverse all anticoagulants that act through this part of the coagulation cascade including anti-FXa DOACs, such as apixaban, edoxaban and rivaroxaban, and indirect FXa inhibitors such as low-molecular-weight heparins. This narrative reviews the development of andexanet alfa and explores its basic science, pharmacokinetics/pharmacodynamics, animal models, and human studies

Histone gene replacement reveals a post-transcriptional role for H3K36 in maintaining metazoan transcriptome fidelity

Histone H3 lysine 36 methylation (H3K36me) is thought to participate in a host of co-transcriptional regulatory events. To study the function of this residue independent from the enzymes that modify it, we used a ‘histone replacement’ system in Drosophila to generate a non-modifiable H3K36 lysine-to-arginine (H3K36R) mutant. We observed global dysregulation of mRNA levels in H3K36R animals that correlates with the incidence of H3K36me3. Similar to previous studies, we found that mutation of H3K36 also resulted in H4 hyperacetylation. However, neither cryptic transcription initiation, nor alternative pre-mRNA splicing, contributed to the observed changes in expression, in contrast with previously reported roles for H3K36me. Interestingly, knockdown of the RNA surveillance nuclease, Xrn1, and members of the CCR4-Not deadenylase complex, restored mRNA levels for a class of downregulated, H3K36me3-rich genes. We propose a post-transcriptional role for modification of replication-dependent H3K36 in the control of metazoan gene expression

Seasonal evolution of Aleutian low pressure systems: Implications for the North Pacific subpolar circulation

The seasonal change in the development of Aleutian low pressure systems from early fall to early winter is analyzed using a combination of meteorological reanalysis fields, satellite sea surface temperature (SST) data, and satellite wind data. The time period of the study is September–December 2002, although results are shown to be representative of the long-term climatology. Characteristics of the storms were documented as they progressed across the North Pacific, including their path, central pressure, deepening rate, and speed of translation. Clear patterns emerged. Storms tended to deepen in two distinct geographical locations—the Gulf of Alaska in early fall and the western North Pacific in late fall. In the Gulf of Alaska, a quasi-permanent “notch” in the SST distribution is argued to be of significance. The signature of the notch is imprinted in the atmosphere, resulting in a region of enhanced cyclonic potential vorticity in the lower troposphere that is conducive for storm development. Later in the season, as winter approaches and the Sea of Okhotsk becomes partially ice covered and cold, the air emanating from the Asian continent leads to enhanced baroclinicity in the region south of Kamchatka. This corresponds to enhanced storm cyclogenesis in that region. Consequently, there is a seasonal westward migration of the dominant lobe of the Aleutian low. The impact of the wind stress curl pattern resulting from these two regions of storm development on the oceanic circulation is investigated using historical hydrography. It is argued that the seasonal bimodal input of cyclonic vorticity from the wind may be partly responsible for the two distinct North Pacific subarctic gyres

Lay and healthcare providers’ experiences to inform future of respectful maternal and newborn care in Tanzania and Malawi: An Appreciative Inquiry

Objectives Disrespectful care, which remains prevalent in low and middle-income countries (LMICs), acts as a barrier to women accessing skilled birth attendance, compromising care when services are available. Building on what was positive in facilities, we aimed to explore lay and healthcare providers’ experience of respectful care to inform future interventions. Setting Five maternity facilities in Mwanza Tanzania and Lilongwe Malawi. Participants 94 participants in Malawi (N=46) and Tanzania (N=48) including 24 women birthing live baby within the previous 12 months; 22 family members and 48 healthcare providers who regularly provided maternity care in the included facilities Design The study was guided by Appreciative Inquiry (AI). Semistructured, one-to-one interviews were conducted between January and December 2019. Interviews were audio-recorded, translated where necessary, transcribed verbatim, and analysed using the framework approach. Results Four main themes describing participants positive experience and their vision of respectful care were identified: (1) empathic healthcare provider–woman interactions including friendly welcome and courteous language, well-timed appropriate care and information sharing, (2) an enabling environment, characterised by improvement of physical environment, the use of screens, curtains and wall partitions for privacy, availability of equipment and provision of incentives to staff, (3) supportive leadership demonstrated by the commitment of the government and facility leaders to provision of respectful care, ensuring availability of guidelines and policies, supportive supervision, reflective discussion and paying staff salaries timely, (4) providers’ attitudes and behaviours characterised by professional values through readiness, compassionate communication and commitment. Conclusion The positive experiences of service users, families and healthcare providers provided insight into key drivers of respectful care in facilities in Tanzania and Malawi. Interventions targeting improved environment and privacy, healthcare provider communication and developing positive leadership structures in facilities could provide the basis for sustained improvement in respectful and dignified maternal and newborn care in LMICs

The acetylation of transcription factor HBP1 by p300/CBP enhances p16INK4A expression

HBP1 is a sequence-specific DNA-binding transcription factor with many important biological roles. It activates or represses the expression of some specific genes during cell growth and differentiation. Previous studies have exhibited that HBP1 binds to p16INK4A promoter and activates p16INK4A expression. We found that trichostatin A (TSA), an inhibitor of HDAC (histone deacetylase), induces p16INK4A expression in an HBP1-dependent manner. This result was drawn from a transactivation experiment by measuring relative luciferase activities of p16INK4A promoter with HBP1-binding site in comparison with that of the wild-type p16INK4A promoter by transient cotransfection with HBP1 into HEK293T cells and 2BS cells. HBP1 acetylation after TSA treatment was confirmed by immunoprecipitation assay. Our data showed that HBP1 interacted with histone acetyltransferase p300 and CREB-binding protein (CBP) and also recruited p300/CBP to p16INK4A promoter. HBP1 was acetylated by p300/CBP in two regions: repression domain (K297/305/307) and P domain (K171/419). Acetylation of Repression domain was not required for HBP1 transactivation on p16INK4A. However, luciferase assay and western blotting results indicate that acetylation of P domain, especially K419 acetylation is essential for HBP1 transactivation on p16INK4A. As assayed by SA-beta-gal staining, the acetylation of HBP1 at K419 enhanced HBP1-induced premature senescence in 2BS cells. In addition, HDAC4 repressed HBP1-induced premature senescence through permanently deacetylating HBP1. We conclude that our data suggest that HBP1 acetylation at K419 plays an important role in HBP1-induced p16INK4A expression

Winter mixed layer development in the central Irminger Sea : the effect of strong, intermittent wind events

Author Posting. © American Meteorological Society, 2008. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 38 (2008): 541-565, doi:10.1175/2007JPO3678.1.The impact of the Greenland tip jet on the wintertime mixed layer of the southwest Irminger Sea is investigated using in situ moored profiler data and a variety of atmospheric datasets. The mixed layer was observed to reach 400 m in the spring of 2003 and 300 m in the spring of 2004. Both of these winters were mild and characterized by a low North Atlantic Oscillation (NAO) index. A typical tip jet event is associated with a low pressure system that is advected by upper-level steering currents into the region east of Cape Farewell and interacts with the high topography of southern Greenland. Heat flux time series for the mooring site were constructed that include the enhancing influence of the tip jet events. This was used to force a one-dimensional mixed layer model, which was able to reproduce the observed envelope of mixed layer deepening in both winters. The deeper mixed layer of the first winter was largely due to a higher number of robust tip jet events, which in turn was caused by the steering currents focusing more storms adjacent to southern Greenland. Application of the mixed layer model to the winter of 1994–95, a period characterized by a high-NAO index, resulted in convection exceeding 1700 m. This prediction is consistent with hydrographic data collected in summer 1995, supporting the notion that deep convection can occur in the Irminger Sea during strong winters.KV and RP were supported by National Science Foundation Grant OCE-0450658. GWKM was supported by the Canadian Foundation for Climate and Atmospheric Sciences. MHR was supported by the Nordic Council of Ministers (West-Nordic Ocean Climate)

Report on IOCCG Workshop Phytoplankton Composition from Space: towards a validation\ud strategy for satellite algorithms

The IOCCG-supported workshop “Phytoplankton Composition from Space: towards a validation strategy for satellite algorithms” was organized as a follow-up to the Phytoplankton Functional Types from Space splinter session, held at the International Ocean Colour Science Meeting (Germany, 2013). The specific goals of the workshop were to: 1. Provide a summary of the status of activities from relevant IOCCG working groups, the 2nd PFT intercomparison working group, PFT validation data sets and other research developments. 2. Provide a PFT validation strategy that considers the different applications of PFT products: and seeks community consensus on datasets and analysis protocols. 3. Discuss possibilities for sustaining ongoing PFT algorithm validation and intercomparison activities. The workshop included 15 talks, breakout sessions and plenary discussions. Talks covered community algorithm intercomparison activity updates, review of established and novel methods for PFT validation, validation activities for specific applications and space-agency requirements for PFT products and validation. These were followed by general discussions on (a) major recommendations for global intercomparison initiative in respect to validation, intercomparison and user’s guide; (b) developing a community consensus on which data sets for validation are optimal and which measurement and analysis protocols should be followed to support sustained validation of PFT products considering different applications; (c) the status of different validation data bases and measurement protocols for different PFT applications, and (d) engagement of the various user communities for PFT algorithms in developing PFT product specifications. From these discussions, two breakout groups provided in depth discussion and recommendations on (1) validation of current algorithms and (2) work plan to prepare for validation of future missions. Breakout group 1 provided an action list for progressing the current international community validation and intercomparison activity. Breakout group 2 provided the following recommendations towards developing a future validation strategy for satellite PFT products: 1. Establish a number of validation sites that maintain measurements of a key set of variables. 2. This set of variables should include: • Phytoplankton pigments from HPLC, phycobilins from spectrofluorometry • Phytoplankton cell counts and ID, volume / carbon estimation and imaging (e.g. from flow cytometry, FlowCam, FlowCytobot type technologies) • Inherent optical properties (e.g. absorption, backscattering, VSF) • Hyperspectral radiometry (both above and in-water) • Particle size distribution • Size-fractionated measurements of pigments and absorption • Genetic / -omics data 3. Undertake an intercomparison of methods / instruments over several years at a few sites to understand our capabilities to fully characterize the phytoplankton community. 4. Organise workshops to address the following topics: • Techniques for particle analysis, characterization and classification • Engagement with modellers and understanding end-user requirements • Data storage and management, standards for data contributors, data challenges In conclusion, the workshop was assessed to have fulfilled its goals. A follow-on meeting will be organized during the International Ocean Colour Science Meeting 2015 in San Francisco. Specific follow-on actions are listed at the end of the report

The western North Atlantic shelfbreak current system in summer

Author Posting. © American Meteorological Society, 2007. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography. 37 (2007): 2509-2533, doi:10.1175/JPO3123.1.Twelve years of historical hydrographic data, spanning the period 1990–2001, are analyzed to examine the along-stream evolution of the western North Atlantic Ocean shelfbreak front and current, following its path between the west coast of Greenland and the Middle Atlantic Bight. Over 700 synoptic sections are used to construct a mean three-dimensional description of the summer shelfbreak front and to quantify the along-stream evolution in properties, including frontal strength and grounding position. Results show that there are actually two fronts in the northern part of the domain—a shallow front located near the shelf break and a deeper front centered in the core of Irminger Water over the upper slope. The properties of the deeper Irminger front erode gradually to the south, and the front disappears entirely near the Grand Banks of Newfoundland. The shallow shelfbreak front is identifiable throughout the domain, and its properties exhibit large variations from north to south, with the largest changes occurring near the Tail of the Grand Banks. Despite these structural changes, and large variations in topography, the foot of the shelfbreak front remains within 20 km of the shelf break. The hydrographic sections are also used to examine the evolution of the baroclinic velocity field and its associated volume transport. The baroclinic velocity structure consists of a single velocity core that is stronger and penetrates deeper where the Irminger front is present. The baroclinic volume transport decreases by equal amounts at the southern end of the Labrador Shelf and at the Tail of the Grand Banks. Overall, the results suggest that the Grand Banks is a geographically critical location in the North Atlantic shelfbreak system.This work was supported by the National Science Foundation under Grants OCE00- 95261 (PF) and OCE-0450658 (RP)

SOX2 Drives Bronchial Dysplasia in a Novel Organotypic Model of Early Human Squamous Lung Cancer

Rationale Improving the early detection and chemoprevention of lung cancer are key to improving outcomes. The pathobiology of early squamous lung cancer is poorly understood. We have shown that amplification of SOX2 is an early and consistent event in the pathogenesis of this disease but its functional oncogenic potential remains uncertain. We tested the impact of deregulated SOX2 expression in a novel organotypic system that recreates the molecular and microenvironmental context in which squamous carcinogenesis occurs. Objectives 1) To develop an in vitro model of bronchial dysplasia that recapitulates key molecular and phenotypic characteristics of the human disease 2) To test the hypothesis that SOX2 deregulation is a key early event in the pathogenesis of bronchial dysplasia 3) To use the model for studies on pathogenesis and chemoprevention Methods We engineer the inducible activation of oncogenes in immortalised bronchial epithelial cells. We use 3-dimensional tissue culture to build an organotypic model of bronchial dysplasia. Measurements and Main Results We recapitulate human bronchial dysplasia in vitro. SOX2 deregulation drives dysplasia, and loss of TP53 is a co-operating genetic event that potentiates the dysplastic phenotype. Deregulated SOX2 alters critical genes implicated in hallmarks of cancer progression. Targeted inhibition of AKT prevents the initiation of the dysplastic phenotype. Conclusion In the appropriate genetic and microenvironmental context acute deregulation of SOX2 drives bronchial dysplasia. This confirms it’s oncogenic potential in human cells and affords novel insights into the impact of SOX2 deregulation. This model can be used to test therapeutic agents aimed at chemoprevention.This work is supported by the Wellcome Trust. FM is a Wellcome Trust Intermediate Clinical Fellow (WT097143MA). TDL and GIE are supported by Cancer Research UK (C4750/A12077 and C4750/A19013). This work was also supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. PL is supported by MRC Programme Grant G1100238. RCR and DMR are supported in part by the NIHR Biomedical Research Centre in Cambridge and the Cambridge Cancer Centre