Given the importance of deregulated phosphoinositide (PI) signaling in leukemic hematopoiesis, genes coding for proteins that regulate PI metabolism may have significant and as yet unappreciated ...roles in leukemia. We performed a targeted knockdown (KD) screen of PI modulator genes in human acute myeloid leukemia (AML) cells and identified candidates required to sustain proliferation or prevent apoptosis. One of these, the lipid kinase phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A) regulates cellular levels of phosphatidylinositol-5-phosphate (PtsIns5P) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂). We found PIP4K2A to be essential for the clonogenic and leukemia-initiating potential of human AML cells, and for the clonogenic potential of murine MLL-AF9 AML cells. Importantly, PIP4K2A is also required for the clonogenic potential of primary human AML cells. Its KD results in accumulation of the cyclin-dependent kinase inhibitors CDKN1A and CDKN1B, G₁ cell cycle arrest and apoptosis. Both CDKN1A accumulation and apoptosis were partially dependent on activation of the mTOR pathway. Critically, however, PIP4K2A KD in normal hematopoietic stem and progenitor cells, both murine and human, did not adversely impact either clonogenic or multilineage differentiation potential, indicating a selective dependency that we suggest may be the consequence of the regulation of different transcriptional programs in normal versus malignant cells. Thus, PIP4K2A is a novel candidate therapeutic target in myeloid malignancy.
The BGOOD experiment at ELSA Jude, TC; Beck, R; Braghieri, A ...
Journal of physics. Conference series,
09/2023, Letnik:
2586, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract
The BGOOD photoproduction experiment accesses forward meson angles and low momentum exchange kinematics in the
uds
sector, which may be sensitive to molecular-like hadron structure. Recent ...results are presented, including strangeness photoproduction at forward meson angles, and π
0
π
0
coherent photoproduction off the deuteron.
The basaltic, phreatomagmatic eruption of Grímsvötn volcano, Iceland, in November 2004 (G2004) lasted for 5 days, during which time two separate vents were active. Significant deposition of tephra ...occurred in the first 45 h only. We have subdivided the deposit into seven units (A–G) on the basis of differences in texture, grain size and componentry, and the presence of sharp contacts between the layers. The distribution of tephra lobes was used to infer the vent of origin for each unit. The G2004 deposit is poorly sorted overall and consists of non-vesicular to highly vesicular juvenile components. Units A and B comprise almost exclusively non- to poorly vesicular glass fragments, whereas units C–G contain at least 30 vol.% highly vesicular pumice. The proportion of non-juvenile fragments increases significantly in the final unit (unit F) of the main phase; non-juvenile fragments are restricted to the coarse (>0 Φ) fraction of the deposit. Main phase units C and E account for 80% of the total deposit volume, including the entire distal portion, and are interpreted to represent a mixture of (1) a widely dispersed component that fell from the upper margins of a strongly inclined (∼45°), 6–10 km high plume and (2) a locally dispersed (<3 km from source) component originating from pyroclastic density currents and minor tephra jets.
The spin polarizabilities of the nucleon describe how the spin of the nucleon responds to an incident polarized photon. The most model-independent way to extract the nucleon spin polarizabilities is ...through polarized Compton scattering. Double-polarized Compton scattering asymmetries on the proton were measured in the Δ(1232) region using circularly polarized incident photons and a transversely polarized proton target at the Mainz Microtron. Fits to asymmetry data were performed using a dispersion model calculation and a baryon chiral perturbation theory calculation, and a separation of all four proton spin polarizabilities in the multipole basis was achieved. The analysis based on a dispersion model calculation yields γ(E1E1)=-3.5±1.2, γ(M1M1)=3.16±0.85, γ(E1M2)=-0.7±1.2, and γ(M1E2)=1.99±0.29, in units of 10(-4) fm(4).
We report dynamic changes in the priorities for strategic risks faced by international water utilities over a 10year period, as cited by managers responsible for managing them. A content analysis of ...interviews with three cohorts of risk managers in the water sector was undertaken. Interviews probed the focus risk managers' were giving to strategic risks within utilities, as well as specific questions on risk analysis tools (2005); risk management cultures (2011) and the integration of risk management with corporate decision-making (2015). The coding frequency of strategic (business, enterprise, corporate) risk terms from 18 structured interviews (2005) and 28 semi-structured interviews (12 in 2011; 16 in 2015) was used to appraise changes in the perceived importance of strategic risks within the sector. The aggregated coding frequency across the study period, and changes in the frequency of strategic risks cited at three interview periods identified infrastructure assets as the most significant risk over the period and suggests an emergence of extrinsic risk over time. Extended interviews with three utility risk managers (2016) from the UK, Canada and the US were then used to contextualise the findings. This research supports the ongoing focus on infrastructure resilience and the increasing prevalence of extrinsic risk within the water sector, as reported by the insurance sector and by water research organisations. The extended interviews provided insight into how strategic risks are now driving the implementation agenda within utilities, and into how utilities can secure tangible business value from proactive risk governance. Strategic external risks affecting the sector are on the rise, involve more players and are less controllable from within a utility's own organisational boundaries. Proportionate risk management processes and structures provide oversight and assurance, whilst allowing a focus on the tangible business value that comes from managing strategic risks well.
•A content analysis of interviews with risk managers in international water utilities was completed.•The analysis was supplemented with extended interviews with utility risk managers.•Infrastructure risks have remained paramount throughout 2005–2015.•Extrinsic risks are gaining significance with organisational implications.•Utilities face hesitancy from managers about perceived barriers to implementation.
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γ
p
→
K
+
Λ
differential cross sections and recoil polarisation data from threshold for extremely forward angles are presented. The measurements were performed at the BGOOD experiment at ELSA, ...utilising the high angular and momentum resolution forward spectrometer for charged particle identification. The high statistics and forward angle acceptance enables the extraction of the cross section as the minimum momentum transfer to the recoiling hyperon is approached.
A review of recent results in strangeness photoproduction is presented, in preparation for experimental proposals for the new BGO-OD experiment at the ELSA facilty, Bonn. Cross section measurements ...and polarisation observables in γ(p, K+)Λ are discussed, and the relation to these measurements and what can be gleaned from neutral kaon photoproduction. Recent cross section data for γ(p, K0)Σ+ and γ(n, K0)Λ is presented, and measurement of the Λ(1405) lineshape from Σπ decays and comparison to theory. Hypernuclei are introduced, and what can be acheived using a real photon beam.
Quasi-free photoproduction of πη-pairs has been investigated from threshold up to incident photon energies of 1.4 GeV, respectively up to photon-nucleon invariant masses up to 1.9 GeV. Total cross ...sections, angular distributions, invariant-mass distributions of the πη and meson-nucleon pairs, and beam helicity asymmetries have been measured for the reactions γp → pπ0η, γn → nπ0η, γp → nπ+η, and γn → pπ–η from nucleons bound inside the deuteron. For the γp initial-state data for free protons have also been analyzed. Finally, the total cross sections for quasi-free production of π0η pairs from nucleons bound in 3He nuclei have been investigated in view of final state interaction (FSI) effects. The experiments were performed at the tagged photon beam facility of the Mainz MAMI accelerator using an almost 4π covering electromagnetic calorimeter composed of the Crystal Ball and TAPS detectors. The shapes of all differential cross section data and the asymmetries are very similar for protons and neutrons and agree with the conjecture that the reactions are dominated by the sequential Δ *3/2– → ηΔ(1232) → πηN decay chain, mainly with Δ(1700)3/2– and Δ(1940)3/2–. The ratios of the magnitude of the total cross sections also agree with this assumption. Furthermore, the absolute magnitudes of the cross sections are reduced by FSI effects with respect to free proton data.
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