Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype

© 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Fanconi anemia (FA) is a rare disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer. Patients harboring X-linked FANCB pathogenic variants usually present with severe congenital malformations resembling VACTERL syndrome with hydrocephalus. Methods: We employed the diepoxybutane (DEB) test for FA diagnosis, arrayCGH for detection of duplication, targeted capture and next-gen sequencing for defining the duplication breakpoint, PacBio sequencing of full-length FANCB aberrant transcript, FANCD2 ubiquitination and foci formation assays for the evaluation of FANCB protein function by viral transduction of FANCB- cells with lentiviral FANCB WT and mutant expression constructs, and droplet digital PCR for quantitation of the duplication in the genomic DNA and cDNA. Results: We describe here an FA-B patient with a mild phenotype. The DEB diagnostic test for FA revealed somatic mosaicism. We identified a 9154 bp intragenic duplication in FANCB, covering the first coding exon 3 and the flanking regions. A four bp homology (GTAG) present at both ends of the breakpoint is consistent with microhomology-mediated duplication mechanism. The duplicated allele gives rise to an aberrant transcript containing exon 3 duplication, predicted to introduce a stop codon in FANCB protein (p.A319*). Duplication levels in the peripheral blood DNA declined from 93% to 7.9% in the span of eleven years. Moreover, the patient fibroblasts have shown 8% of wild-type (WT) allele and his carrier mother showed higher than expected levels of WT allele (79% vs. 50%) in peripheral blood, suggesting that the duplication was highly unstable. Conclusion: Unlike sequence point variants, intragenic duplications are difficult to precisely define, accurately quantify, and may be very unstable, challenging the proper diagnosis. The reversion of genomic duplication to the WT allele results in somatic mosaicism and may explain the relatively milder phenotype displayed by the FA-B patient described here

Finite-Temperature Transport in Finite-Size Hubbard Rings in the Strong-Coupling Limit

We study the current, the curvature of levels, and the finite temperature charge stiffness, D(T,L), in the strongly correlated limit, U>>t, for Hubbard rings of L sites, with U the on-site Coulomb repulsion and t the hopping integral. Our study is done for finite-size systems and any band filling. Up to order t we derive our results following two independent approaches, namely, using the solution provided by the Bethe ansatz and the solution provided by an algebraic method, where the electronic operators are represented in a slave-fermion picture. We find that, in the U=\infty case, the finite-temperature charge stiffness is finite for electronic densities, n, smaller than one. These results are essencially those of spinless fermions in a lattice of size L, apart from small corrections coming from a statistical flux, due to the spin degrees of freedom. Up to order t, the Mott-Hubbard gap is \Delta_{MH}=U-4t, and we find that D(T) is finite for n<1, but is zero at half-filling. This result comes from the effective flux felt by the holon excitations, which, due to the presence of doubly occupied sites, is renormalized to \Phi^{eff}=\phi(N_h-N_d)/(N_d+N_h), and which is zero at half-filling, with N_d and N_h being the number of doubly occupied and empty lattice sites, respectively. Further, for half-filling, the current transported by any eigenstate of the system is zero and, therefore, D(T) is also zero.Comment: 15 pages and 6 figures; accepted for PR

Mapping IR Enhancements in Closely Interacting Spiral-Spiral Pairs. I. ISO~CAM and ISO~SWS Observations

Mid-infrared (MIR) imaging and spectroscopic observations are presented for a well defined sample of eight closely interacting (CLO) pairs of spiral galaxies that have overlapping disks and show enhanced far-infrared (FIR) emission. The goal is to study the star formation distribution in CLO pairs, with special emphasis on the role of 'overlap starbursts'. Observations were made with the Infrared Space Observatory (ISO) using the CAM and SWS instruments. The ISO~CAM maps, tracing the MIR emission of warm dust heated by young massive stars, are compared to new ground based H$\alpha$ and R-band images. We identify three possible subgroups in the sample, classified according to the star formation morphology: (1) advanced mergers (Arp~157, Arp~244 and Arp~299), (2) severely disturbed systems (Arp~81 and Arp~278), and (3) less disturbed systems (Arp~276, KPG 347 and KPG 426). Localized starbursts are detected in the overlap regions in all five pairs of subgroups (1) and (2), suggesting that they are a common property in colliding systems. Except for Arp~244, the 'overlap starburst' is usually fainter than the major nuclear starburst in CLO pairs. Star formation in 'less disturbed systems' is often distributed throughout the disks of both galaxies with no 'overlap starburst' detected in any of them. These systems also show less enhanced FIR emission, suggesting that they are in an earlier interaction stage than pairs of the other two subgroups where the direct disk collisions have probably not yet occurred.Comment: 27 pages text, 4 JPEG figures, 3 PS figures. To be accepted by ApJ. High quality figures (included in a PS file of the paper) can be found in http://spider.ipac.caltech.edu/staff/cxu/papers/ss_iso.ps.g

The burden of diabetes mellitus during pregnancy in low- and middle-income countries : a systematic review

Peer reviewedPublisher PD

Modulation of Transmission Spectra of Anodized Alumina Membrane Distributed Bragg Reflector by Controlling Anodization Temperature

We have successfully prepared anodized alumina membrane distributed Bragg reflector (DBR) using electrochemical anodization method. The transmission peak of this distributed Bragg reflector could be easily and effectively modulated to cover almost any wavelength range of the whole visible spectrum by adjusting anodization temperature

Controlled assembly of SNAP-PNA-fluorophore systems on DNA templates to produce fluorescence resonance energy transfer

The SNAP protein is a widely used self-labeling tag that can be used for tracking protein localization and trafficking in living systems. A model system providing controlled alignment of SNAP-tag units can provide a new way to study clustering of fusion proteins. In this work, fluorescent SNAP-PNA conjugates were controllably assembled on DNA frameworks forming dimers, trimers, and tetramers. Modification of peptide nucleic acid (PNA) with the O6-benzyl guanine (BG) group allowed the generation of site-selective covalent links between PNA and the SNAP protein. The modified BG-PNAs were labeled with fluorescent Atto dyes and subsequently chemo-selectively conjugated to SNAP protein. Efficient assembly into dimer and oligomer forms was verified via size exclusion chromatography (SEC), electrophoresis (SDS-PAGE), and fluorescence spectroscopy. DNA directed assembly of homo- and hetero-dimers of SNAP-PNA constructs induced homo- and hetero-FRET, respectively. Longer DNA scaffolds controllably aligned similar fluorescent SNAP-PNA constructs into higher oligomers exhibiting homo-FRET. The combined SEC and homo-FRET studies indicated the 1:1 and saturated assemblies of SNAP-PNA-fluorophore:DNA formed preferentially in this system. This suggested a kinetic/stoichiometric model of assembly rather than binomially distributed products. These BG-PNA-fluorophore building blocks allow facile introduction of fluorophores and/or assembly directing moieties onto any protein containing SNAP. Template directed assembly of PNA modified SNAP proteins may be used to investigate clustering behavior both with and without fluorescent labels which may find use in the study of assembly processes in cells

Process Simulation and Control Optimization of a Blast Furnace Using Classical Thermodynamics Combined to a Direct Search Algorithm

Several numerical approaches have been proposed in the literature to simulate the behavior of modern blast furnaces: finite volume methods, data-mining models, heat and mass balance models, and classical thermodynamic simulations. Despite this, there is actually no efficient method for evaluating quickly optimal operating parameters of a blast furnace as a function of the iron ore composition, which takes into account all potential chemical reactions that could occur in the system. In the current study, we propose a global simulation strategy of a blast furnace, the 5-unit process simulation. It is based on classical thermodynamic calculations coupled to a direct search algorithm to optimize process parameters. These parameters include the minimum required metallurgical coke consumption as well as the optimal blast chemical composition and the total charge that simultaneously satisfy the overall heat and mass balances of the system. Moreover, a Gibbs free energy function for metallurgical coke is parameterized in the current study and used to fine-tune the simulation of the blast furnace. Optimal operating conditions and predicted output stream properties calculated by the proposed thermodynamic simulation strategy are compared with reference data found in the literature and have proven the validity and high precision of this simulation

Deletion of Munc18-1 in 5-HT Neurons Results in Rapid Degeneration of the 5-HT System and Early Postnatal Lethality

The serotonin (5-HT) system densely innervates many brain areas and is important for proper brain development. To specifically ablate the 5-HT system we generated mutant mice carrying a floxed Munc18-1 gene and Cre recombinase driven by the 5-HT-specific serotonin reuptake transporter (SERT) promoter. The majority of mutant mice died within a few days after birth. Immunohistochemical analysis of brains of these mice showed that initially 5-HT neurons are formed and the cortex is innervated with 5-HT projections. From embryonic day 16 onwards, however, 5-HT neurons started to degenerate and at postnatal day 2 hardly any 5-HT projections were present in the cortex. The 5-HT system of mice heterozygous for the floxed Munc18-1 allele was indistinguishable from control mice. These data show that deletion of Munc18-1 in 5-HT neurons results in rapid degeneration of the 5-HT system and suggests that the 5-HT system is important for postnatal survival

A recurrent truncating germline mutation in the BRIP1/FANCJ gene and susceptibility to prostate cancer

Although prostate cancer (PrCa) is one of the most common cancers in men in Western countries, little is known about the inherited factors that influence PrCa risk. On the basis of the fact that BRIP1/FANCJ interacts with BRCA1 and functions as a regulator of DNA double-strand break repair pathways, and that germline mutations within the BRIP1/FANCJ gene predispose to breast cancer, we chose this gene as a candidate for mutation screening in familial and young-onset PrCa cases. We identified a truncating mutation, R798X, in the BRIP1/FANCJ gene in 4 out of 2714 UK PrCa cases enriched for familial (2 out of 641; 0.3%) and young-onset cases (2 out of 2073; 0.1%). On screening 2045 controls from the UK population, we found one R798X sequence alteration (0.05%; odds ratio 2.4 (95% CI 0.25–23.4)). In addition, using our data from a genome-wide association study, we analysed 25 SNPs in the genomic region of the BRIP1/FANCJ gene. Two SNPs showed evidence of association with familial and young-onset PrCa (rs6504074; Ptrend=0.04 and rs8076727; Ptrend=0.01). These results suggest that truncating mutations in BRIP1/FANCJ might confer an increased risk of PrCa and common SNPs might also contribute to the alteration of risk, but larger case–control series will be required to confirm or refute this association