^{31}P and ^{75}As NMR evidence for a residual density of states at zero energy in superconducting BaFe_2(As_{0.67}P_{0.33})_2

^{31}P and ^{75}As NMR measurements were performed in superconducting BaFe_2(As_{0.67}P_{0.33})_2 with T_c = 30 K. The nuclear-spin-lattice relaxation rate T_1^{-1} and the Knight shift in the normal state indicate the development of antiferromagnetic fluctuations, and T_1^{-1} in the superconducting (SC) state decreases without a coherence peak just below T_c, as observed in (Ba_{1-x}K_{x})Fe_2As_2. In contrast to other iron arsenide superconductors, the T_1^{-1} \propto T behavior is observed below 4K, indicating the presence of a residual density of states at zero energy. Our results suggest that strikingly different SC gaps appear in BaFe_2(As_{1-x}P_{x})_2 despite a comparable T_c value, an analogous phase diagram, and similar Fermi surfaces to (Ba_{1-x}K_{x})Fe_2As_2.Comment: 4 pages, 5 figure

Directed Differentiation of Patient-Specific Induced Pluripotent Stem Cells Identifies the Transcriptional Repression and Epigenetic Modification of NKX2-5, HAND1, and NOTCH1 in Hypoplastic Left Heart Syndrome

The genetic basis of hypoplastic left heart syndrome (HLHS) remains unknown, and the lack of animal models to reconstitute the cardiac maldevelopment has hampered the study of this disease. This study investigated the altered control of transcriptional and epigenetic programs that may affect the development of HLHS by using disease-specific induced pluripotent stem (iPS) cells. Cardiac progenitor cells (CPCs) were isolated from patients with congenital heart diseases to generate patient-specific iPS cells. Comparative gene expression analysis of HLHS- and biventricle (BV) heart-derived iPS cells was performed to dissect the complex genetic circuits that may promote the disease phenotype. Both HLHS- and BV heart-derived CPCs were reprogrammed to generate disease-specific iPS cells, which showed characteristic human embryonic stem cell signatures, expressed pluripotency markers, and could give rise to cardiomyocytes. However, HLHS-iPS cells exhibited lower cardiomyogenic differentiation potential than BV-iPS cells. Quantitative gene expression analysis demonstrated that HLHS-derived iPS cells showed transcriptional repression of NKX2-5, reduced levels of TBX2 and NOTCH/HEY signaling, and inhibited HAND1/2 transcripts compared with control cells. Although both HLHS-derived CPCs and iPS cells showed reduced SRE and TNNT2 transcriptional activation compared with BV-derived cells, co-transfection of NKX2-5, HAND1, and NOTCH1 into HLHS-derived cells resulted in synergistic restoration of these promoters activation. Notably, gain- and loss-of-function studies revealed that NKX2-5 had a predominant impact on NPPA transcriptional activation. Moreover, differentiated HLHS-derived iPS cells showed reduced H3K4 dimethylation as well as histone H3 acetylation but increased H3K27 trimethylation to inhibit transcriptional activation on the NKX2-5 promoter. These findings suggest that patient-specific iPS cells may provide molecular insights into complex transcriptional and epigenetic mechanisms, at least in part, through combinatorial expression of NKX2-5, HAND1, and NOTCH1 that coordinately contribute to cardiac malformations in HLHS

Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy

Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)–mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy

Spatial Evolution of Wave‐Particle Interaction Region Deduced From Flash‐Type Auroras and Chorus‐Ray Tracing

In-situ observations of spatial variations of the wave-particle interaction region require a large number of satellite probes. As an alternative, flash-type auroras, a kind of pulsating aurora, driven by discrete chorus elements, can be used to investigate the interaction region with a high spatial resolution. We estimated the spatial extent of wave-particle interaction region from ground-based observations of flash aurora at Gakona (62.39°N, 214.78°E), Alaska at subauroral latitudes, and found that the auroral expansion was predominantly to the low-latitude side. The spatial displacement is thought to be caused by the propagation effects of chorus waves in the magnetosphere. Using ray tracing analysis to take into account chorus wave propagation, we reconstructed the spatiotemporal evolution of the volume emission rate and confirmed that the predominant expansion is toward the lower-latitude side in the ionosphere. This study shows that chorus wave propagation in the magnetosphere gives new insight for characterizing the transverse size (across the geomagnetic field line) of wave-particle interaction regions. The calculated spatial scale of the column auroral emission shows a correlation with the magnetic latitude of the resonance region at magnetic latitudes within 10° of the equatorial plane of the magnetosphere. Our results suggest that the spatial scale of a flash aurora is indirectly related to the chorus amplitude because the latitudinal range of the wave-particle interaction is important for the growth of wave amplitude

Asymmetrically traveling auroral surges in the northern and southern hemisphere

The Tenth Symposium on Polar Science/Ordinary sessions: [OS] Space and upper atmospheric sciences, Wed. 4 Dec. / Institute of Statistics and Mathematics (ISM) Seminar room 2 (D304) (3rd floor

Postazacitidine clone size predicts long-term outcome of patients with myelodysplastic syndromes and related myeloid neoplasms

Azacitidine is a mainstay of therapy for MDS-related diseases. The purpose of our study is to elucidate the effect of gene mutations on hematological response and overall survival (OS), particularly focusing on their post-treatment clone size. We enrolled a total of 449 patients with MDS or related myeloid neoplasms. They were analyzed for gene mutations in pre- (n=449) and post- (n=289) treatment bone marrow samples using targeted-capture sequencing to assess the impact of gene mutations and their post-treatment clone size on treatment outcomes. In Cox proportional hazard modeling, multi-hit TP53 mutation (HR, 2.03; 95% CI, 1.42-2.91; P<.001), EZH2 mutation (HR, 1.71; 95% CI, 1.14-2.54; P=.009), and DDX41 mutations (HR, 0.33; 95% CI, 0.17-0.62; P<.001), together with age, high-risk karyotypes, low platelet, and high blast counts, independently predicted OS. Post-treatment clone size accounting for all drivers significantly correlated with International Working Group (IWG)-response (P<.001, trend test), except for that of DDX41-mutated clones, which did not predict IWG-response. Combined, IWG-response and post-treatment clone size further improved the prediction of the original model and even that of a recently proposed molecular prediction model, IPSS-M (c-index, 0.653 vs 0.688; P<.001, likelihood ratio test). In conclusion, evaluation of post-treatment clone size, together with pre-treatment mutational profile as well as IWG-response have a role in better prognostication of azacitidine-treated myelodysplasia patients

Neurocytotoxic effects of iron-ions on the developing brain measured in vivo using medaka (Oryzias latipes), a vertebrate model

Purpose: Exposure to heavy-ion radiation is considered a critical health risk on long-term space missions. The developing central nervous system (CNS) is a highly radiosensitive tissue; however, the biological effects of heavy-ion radiation, which are greater than those of low-linear energy transfer (LET) radiation, are not well studied, especially in vivo in intact organisms. Here, we examined the effects of iron-ions on the developing CNS using vertebrate organism, fish embryos of medaka (Oryzias latipes)

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response

Gradual suppression of antiferromagnetism in BaFe_{2}(As_{1−x}P_{x})_{2}: Zero-temperature evidence for a quantum critical point

Static and dynamic magnetic properties of lightly P-substituted BaFe_{2}(As_{1−x}P_{x})_{2} were systematically investigated by ^{31}P NMR. The averaged internal magnetic field at the P site in the zero-temperature limit evaluated from the broadening of NMR spectra in the antiferromagnetic (AFM) phase is gradually suppressed toward x∼0.35 with increasing x, which provides definitive evidence for the existence of an AFM quantum critical point (QCP) at x∼0.35. The location of the AFM QCP is consistent with the previous estimation from temperature dependence of spin dynamics in the normal state, and the superconducting transition temperature Tc takes the maximum around the QCP. Our experiments, revealing a signature of a QCP extending up to room temperature, establish BaFe_{2}(As_{1−x}P_{x})_{2} as one of the most accessible systems for unraveling the nature of quantum criticality and the relationship between AFM quantum criticality and unconventional superconductivity