V/A-ATPase is a motor protein that shares a common rotary catalytic mechanism with F
F
ATP synthase. When powered by ATP hydrolysis, the V
domain rotates the central rotor against the A
B
hexamer, ...composed of three catalytic AB dimers adopting different conformations (AB
, AB
, and AB
). Here, we report the atomic models of 18 catalytic intermediates of the V
domain of V/A-ATPase under different reaction conditions, determined by single particle cryo-EM. The models reveal that the rotor does not rotate immediately after binding of ATP to the V
. Instead, three events proceed simultaneously with the 120˚ rotation of the shaft: hydrolysis of ATP in AB
, zipper movement in AB
by the binding ATP, and unzipper movement in AB
with release of both ADP and Pi. This indicates the unidirectional rotation of V/A-ATPase by a ratchet-like mechanism owing to ATP hydrolysis in AB
, rather than the power stroke model proposed previously for F
-ATPase.
Vibrational spectroscopy allows us to understand complex physical and chemical interactions of molecular crystals and liquids such as ammonia, which has recently emerged as a strong hydrogen fuel ...candidate to support a sustainable society. We report inelastic neutron scattering measurement of vibrational properties of ammonia along the solid-to-liquid phase transition with high enough resolution for direct comparisons to ab-initio simulations. Theoretical analysis reveals the essential role of nuclear quantum effects (NQEs) for correctly describing the intermolecular spectrum as well as high energy intramolecular N-H stretching modes. This is achieved by training neural network models using ab-initio path-integral molecular dynamics (PIMD) simulations, thereby encompassing large spatiotemporal trajectories required to resolve low energy dynamics while retaining NQEs. Our results not only establish the role of NQEs in ammonia but also provide general computational frameworks to study complex molecular systems with NQEs.
The flow characteristics of circulating water in a proton exchange membrane (PEM) electrolyzer were experimentally evaluated using a small cell and two-phase flow theory. Results revealed that when a ...two-phase flow of circulating water at the anode is either slug or annular, then mass transport of the water for the anode reaction is degraded, and that the concentration overvoltage increases at higher current density compared to that when the flow is bubbly. In a serpentine-dual flow field, when both phases of the two-phase flow are assumed laminar, then the increase in pressure drop caused by the increase in gas production can be explained relatively well using the Lockhart–Martinelli method with the Chisholm parameter. The optimal flow rate of circulating water was also discussed based on mass balance analysis.
Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural ...rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3′ end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3′ splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).
•A novel EVI1 splice isoform is frequently expressed in inv(3)/t(3;3) leukemia and drives myeloid transformation.•Frequent SF3B1 mutations in inv(3)/t(3;3) leukemia generate a novel EVI1 isoform with an altered second zinc finger domain.
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Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNFα, BAFF ...and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-κB pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment.
Heat and mass transport phenomena in a binary mixture compressible supercritical fluid around the pseudo-critical line were investigated theoretically and numerically. In this study, we focused on ...supercritical artificial air with a composition of 79% nitrogen and 21% oxygen, and investigated the piston effect, the soret effect, and the interactions between these effects. We derived thermo-fluid dynamic equations, in which the compressibility of the fluid, the temperature, the pressure, and the concentration dependences of the entropy were taken into account. The governing equations were solved numerically by using the finite difference method. We could verify that the thermal energy was propagated by the piston effect in a binary mixture supercritical fluid, and the concentration change certainly occurred due to the soret effect. Moreover, we could also estimate the thermal diffusion ratio, which made a direct correlation between the temperature gradient and the concentration gradient.
Amniotic fluid embolism (AFE) is a catastrophic condition in the peripartum period and still remains as a leading cause of maternal death. Although over 80% of cases of AFE cases are accompanied by ...coagulopathy, the pathology of disseminated intravascular coagulation is not well understood not only because of its rarity but also because of the limited availability of laboratory testing in emergent clinical settings. We describe a case of AFE whose characteristic data for coagulation and fibrinolysis were timely depicted with sequential thromboelastography. We believe that the point-of-care, which provides information for both coagulopathy and fibrinolysis, may provide crucial data not only for the treatment of postpartum hemorrhage in daily clinical practice but also for the elucidation of AFE pathophysiology.
Shock-induced collapse of nanobubbles in water is investigated with molecular dynamics simulations based on a reactive force field. We observe a focused jet at the onset of bubble shrinkage and a ...secondary shock wave upon bubble collapse. The jet length scales linearly with the nanobubble radius, as observed in experiments on micron-to-millimeter size bubbles. Shock induces dramatic structural changes, including an ice-VII-like structural motif at a particle velocity of 1 km/s. The incipient ice VII formation and the calculated Hugoniot curve are in good agreement with experimental results.
This paper presents the results of an oxidation behavior study for a thermal barrier coating (TBC) with air plasma sprayed yttria-stabilized zirconia top coat and CoNiCrAlY bond coat deposited using ...low pressure plasma spray (LPPS) and cold spray (CS). The TBC is subjected to isothermal oxidation and creep tests at 900 °C and evaluated using scanning electron microscopy, energy dispersive x-ray spectrometry transmission electron microscopy and electron backscatter diffraction. The thermally grown oxide (TGO) developed in the TBC with the LPPS bond coat was composed of only α-Al
2
O
3
and the TGO developed in the TBC with a CS bond coat is composed of α-Al
2
O
3
and γ-Al
2
O
3
. Despite the presence of this metastable γ phase, the TGO in the CS specimens exhibits a dense microstructure and lower amounts of mixed oxides. The correlation between γ-Al
2
O
3
and the formation of mixed oxides was investigated through the measurement of γ-Al
2
O
3
thickness ratio and mixed oxides coverage ratio. It was found that the mixed oxides coverage ratio is inversely proportional to the γ-Al
2
O
3
thickness ratio.
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