336 research outputs found
Long-term safety and efficacy of pegunigalsidase alfa: A multicenter 6-year study in adult patients with Fabry disease
Purpose: Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD. Methods: In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks. Results: Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed. Conclusion: In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD
Spin dynamics in molecular ring nanomagnets: Significant effect of acoustic phonons and magnetic anisotropies
The nuclear spin-lattice relaxation rate 1/T_1_ is calculated for magnetic
ring clusters by fully diagonalizing their microscopic spin Hamiltonians.
Whether the nearest-neighbor exchange interaction J is ferromagnetic or
antiferromagnetic, 1/T_1_ versus temperature T in ring nanomagnets may be
peaked at around k_B_T=|J| provided the lifetime broadening of discrete energy
levels is in proportion to T^3^. Experimental findings for ferromagnetic and
antiferromagnetic Cu^II^ rings are reproduced with crucial contributions of
magnetic anisotropies as well as acoustic phonons.Comment: 5 pages with 5 figures embedded, to be published in J. Phys. Soc.
Jpn. 75, No. 10 (2006
Slow Relaxation of Spin Structure in Exotic Ferromagnetic Phase of Ising-like Heisenberg Kagome Antiferromagnets
In the corner-sharing lattice, magnetic frustration causes macroscopic
degeneracy in the ground state, which prevents systems from ordering. However,
if the ensemble of the degenerate configuration has some global structure, the
system can have a symmetry breaking phenomenon and thus posses a finite
temperature phase transition. As a typical example of such cases, the magnetic
phase transition of the Ising-like Heisenberg antiferromagnetic model on the
kagome lattice has been studied. There, a phase transition of the
two-dimensional ferromagnetic Ising universality class occurs accompanying with
the uniform spontaneous magnetization. Because of the macroscopic degeneracy in
the ordered phase, the system is found to show an entropy-driven ordering
process, which is quantitatively characterized by the number of ``weathervane
loop''. We investigate this novel type of slow relaxation in regularly
frustrated system.Comment: 4 pages, 6 figure
Associations Between Methylation of Paternally Expressed Gene 3 (PEG3), Cervical Intraepithelial Neoplasia and Invasive Cervical Cancer.
Cytology-based screening for invasive cervical cancer (ICC) lacks sensitivity and specificity to discriminate between cervical intraepithelial neoplasia (CIN) likely to persist or progress from cases likely to resolve. Genome-wide approaches have been used to identify DNA methylation marks associated with CIN persistence or progression. However, associations between DNA methylation marks and CIN or ICC remain weak and inconsistent. Between 2008-2009, we conducted a hospital-based, case-control study among 213 Tanzania women with CIN 1/2/3 or ICC. We collected questionnaire data, biopsies, peripheral blood, cervical scrapes, Human papillomavirus (HPV) and HIV-1 infection status. We assessed PEG3 methylation status by bisulfite pyrosequencing. Multinomial logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI 95%) for associations between PEG3 methylation status and CIN or ICC. After adjusting for age, gravidity, hormonal contraceptive use and HPV infection, a 5% increase in PEG3 DNA methylation was associated with increased risk for ICC (OR = 1.6; 95% CI 1.2-2.1). HPV infection was associated with a higher risk of CIN1-3 (OR = 15.7; 95% CI 5.7-48.6) and ICC (OR = 29.5, 95% CI 6.3-38.4). Infection with high risk HPV was correlated with mean PEG3 differentially methylated regions (DMRs) methylation (r = 0.34 p<0.0001), while the correlation with low risk HPV infection was weaker (r = 0.16 p = 0.047). Although small sample size limits inference, these data support that PEG3 methylation status has potential as a molecular target for inclusion in CIN screening to improve prediction of progression. Impact statement: We present the first evidence that aberrant methylation of the PEG3 DMR is an important co-factor in the development of Invasive cervical carcinoma (ICC), especially among women infected with high risk HPV. Our results show that a five percent increase in DNA methylation of PEG3 is associated with a 1.6-fold increase ICC risk. Suggesting PEG3 methylation status may be useful as a molecular marker for CIN screening to improve prediction of cases likely to progress
Differential Conservation and Divergence of Fertility Genes boule and dazl in the Rainbow Trout
10.1371/journal.pone.0015910PLoS ONE61
DAZL Relieves miRNA-Mediated Repression of Germline mRNAs by Controlling Poly(A) Tail Length in Zebrafish
BACKGROUND:During zebrafish embryogenesis, microRNA (miRNA) miR-430 contributes to restrict Nanos1 and TDRD7 to primordial germ cells (PGCs) by inducing mRNA deadenylation, mRNA degradation, and translational repression of nanos1 and tdrd7 mRNAs in somatic cells. The nanos1 and tdrd7 3'UTRs include cis-acting elements that allow activity in PGCs even in the presence of miRNA-mediated repression. METHODOLOGY/PRINCIPAL FINDINGS:Using a GFP reporter mRNA that was fused with tdrd7 3'UTR, we show that a germline-specific RNA-binding protein DAZ-like (DAZL) can relieve the miR-430-mediated repression of tdrd7 mRNA by inducing poly(A) tail elongation (polyadenylation) in zebrafish. We also show that DAZL enhances protein synthesis via the 3'UTR of dazl mRNA, another germline mRNA targeted by miR-430. CONCLUSIONS/SIGNIFICANCE:Our present study indicated that DAZL acts as an "anti-miRNA factor" during vertebrate germ cell development. Our data also suggested that miRNA-mediated regulation can be modulated on specific target mRNAs through the poly(A) tail control
Emergence of magnetic long-range order in frustrated pyrochlore NdIrO with metal-insulator transition
In this study, we performed powder neutron diffraction and inelastic
scattering measurements of frustrated pyrochlore NdIrO, which
exhibits a metal-insulator transition at a temperature of 33 K.
The diffraction measurements revealed that the pyrochlore has an
antiferromagnetic long-range structure with propagation vector of
(0,0,0) and that it grows with decreasing temperature below 15 K. This
structure was analyzed to be of the all-in all-out type, consisting of highly
anisotropic Nd magnetic moments of magnitude ,
where is the Bohr magneton. The inelastic scattering measurements
revealed that the Kramers ground doublet of Nd splits below . This suggests the appearance of a static internal magnetic field at the
Nd sites, which probably originates from a magnetic order consisting of
Ir magnetic moments. Here, we discuss a magnetic structure model for the
Ir order and the relation of the order to the metal-insulator transition in
terms of frustration.Comment: 6 pages, 1 table, 3 figure
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