Biallelic CSGALNACT1-mutations cause a mild skeletal dysplasia.

Genetic causes of skeletal disorders are manifold and affect, among others, enzymes of bone and connective tissue synthesis pathways. We present a twelve-year-old boy with a mild skeletal dysplasia, hypermobility of joints and axial malalignment of lower limbs and feet. Exome sequencing revealed a biallelic loss of function mutation in CSGALNACT1, which encodes chondroitin sulfate N-acetylgalactosaminyltransferase 1 and plays a major role in the chondroitin sulfate chain biosynthesis and therefore in the synthesis of glycosaminoglycans. Recently, the first case of a pediatric patient with a mild skeletal dysplasia due to a compound heterozygous large intragenic deletion and a damaging missense variant in CSGALNACT1 was reported. We here identify a second case and the first juvenile patient with a homozygous frameshift variant in CSGALNACT1 which corroborates its role in mild and non-progressive skeletal dysplasia with joint laxity.

DESIREE electrospray ion source test bench and setup for collision induced dissociation experiments.

In this paper, we give a detailed description of an electrospray ion source test bench and a single-pass setup for ion fragmentation studies at the Double ElectroStatic Ion Ring ExpEriment infrastructure at Stockholm University. This arrangement allows for collision-induced dissociation experiments at the center-of-mass energies between 10 eV and 1 keV. Charged fragments are analyzed with respect to their kinetic energies (masses) by means of an electrostatic energy analyzer with a wide angular acceptance and adjustable energy resolution.

Experimental determination of the antineutrino spectrum of the fission products of U238.

An experiment was performed at the scientific neutron source FRM II in Garching to determine the cumulative antineutrino spectrum of the fission products of U238. Target foils of natural uranium were irradiated with a thermal and a fast neutron beam and the emitted ß spectra were recorded with a γ-suppressing electron telescope. The obtained ß spectrum of the fission products of U235 was normalized to the data of the magnetic spectrometer BILL. This method strongly reduces systematic errors in the U238 measurement. The ß spectrum of U238 was converted into the corresponding ν¯e spectrum. The final ν¯e spectrum is given in 250 keV bins in the range from 2.875 to 7.625 MeV with an energy-dependent error of 3.5% at 3 MeV, 7.6% at 6 MeV, and ≳14% at energies ≳7 MeV (68% confidence level). Furthermore, an energy-independent uncertainty of ∼3.3% due to the absolute normalization is added. Compared to the generally used summation calculations, the obtained spectrum reveals a spectral distortion of ∼10% but returns the same value for the mean cross section per fission for the inverse beta decay.

Unimolecular dissociation of anthracene and acridine cations: the importance of isomerization barriers for the C2H2 loss and HCN loss channels.

The loss of C(2)H(2) is a low activation energy dissociation channel for anthracene (C(14)H(10)) and acridine (C(13)H(9)N) cations. For the latter ion another prominent fragmentation pathway is the loss of HCN. We have studied these two dissociation channels by collision induced dissociation experiments of 50 keV anthracene cations and protonated acridine, both produced by electrospray ionization, in collisions with a neutral xenon target. In addition, we have carried out density functional theory calculations on possible reaction pathways for the loss of C(2)H(2) and HCN. The mass spectra display features of multi-step processes, and for protonated acridine the dominant first step process is the loss of a hydrogen from the N site, which then leads to C(2)H(2)/HCN loss from the acridine cation. With our calculations we have identified three pathways for the loss of C(2)H(2) from the anthracene cation, with three different cationic products: 2-ethynylnaphthalene, biphenylene, and acenaphthylene. The third product is the one with the overall lowest dissociation energy barrier. For the acridine cation our calculated pathway for the loss of C(2)H(2) leads to the 3-ethynylquinoline cation, and the loss of HCN leads to the biphenylene cation. Isomerization plays an important role in the formation of the non-ethynyl containing products. All calculated fragmentation pathways should be accessible in the present experiment due to substantial energy deposition in the collisions.

The double electrostatic ion ring experiment: a unique cryogenic electrostatic storage ring for merged ion-beams studies.

We describe the design of a novel type of storage device currently under construction at Stockholm University, Sweden, using purely electrostatic focussing and deflection elements, in which ion beams of opposite charges are confined under extreme high vacuum cryogenic conditions in separate "rings" and merged over a common straight section. The construction of this double electrostatic ion ring experiment uniquely allows for studies of interactions between cations and anions at low and well-defined internal temperatures and centre-of-mass collision energies down to about 10 K and 10 meV, respectively. Position sensitive multi-hit detector systems have been extensively tested and proven to work in cryogenic environments and these will be used to measure correlations between reaction products in, for example, electron-transfer processes. The technical advantages of using purely electrostatic ion storage devices over magnetic ones are many, but the most relevant are: electrostatic elements which are more compact and easier to construct; remanent fields, hysteresis, and eddy-currents, which are of concern in magnetic devices, are no longer relevant; and electrical fields required to control the orbit of the ions are not only much easier to create and control than the corresponding magnetic fields, they also set no upper mass limit on the ions that can be stored. These technical differences are a boon to new areas of fundamental experimental research, not only in atomic and molecular physics but also in the boundaries of these fields with chemistry and biology. For examples, studies of interactions with internally cold molecular ions will be particular useful for applications in astrophysics, while studies of solvated ionic clusters will be of relevance to aeronomy and biology.

Electron capture induced dissociation of doubly protonated pentapeptides: dependence on molecular structure and charge separation.

We have studied electron capture induced dissociation of a set of doubly protonated pentapeptides, all composed of one lysine (K) and either four glycine (G) or four alanine (A) residues, as a function of the sequence of these building blocks. Thereby the separation of the two charges, sequestered on the N-terminal amino group and the lysine side chain, is varied. The characteristic cleavage of N-C(α) bonds is observed for all peptides over the whole backbone length, with the charge carrying fragments always containing K. The resulting fragmentation patterns are very similar if G is replaced by A. In the case of [XKXXX+2H](2+) (X=A or G), a distinct feature is observed in the distribution of backbone cleavage fragments and the probability for ammonia loss is drastically reduced. This may be due to an isomer with an amide oxygen as protonation site giving rise to the observed increase in breakage at a specific site in the molecule. For the other peptides, a correlation with the distance between amide oxygen and the charge at the lysine side chain has been found. This may be an indication that it is only the contribution from this site to the charge stabilization of the amide π(*) orbitals which determines relative fragment intensities. For comparison, complexes with two crown ether molecules have been studied as well. The crown ether provides a shielding of the charge and prevents the peptide from folding and internal hydrogen bonding, which leads to a more uniform fragmentation behavior.

Two-center double-capture interference in fast He2+ + H2 collisions.

We report the first observation of Young-type interference effects in a two-electron transfer process. These effects change strongly as the projectile velocity changes in fast (1.2 and 2.0 MeV) He(2+) + H(2) collisions as manifested in strong variations of the double-electron capture rates with the H(2) orientation. This is consistent with fully quantum mechanical calculations, which ignore sequential electron transfer, and a simple projectile de Broglie wave picture assuming that two-electron transfer probabilities are higher in collisions where the projectile passes close to either one of the H(2) nuclei.

Evidence of wave-particle duality for single fast hydrogen atoms.

We report the direct observation of interference effects in a Young's double-slit experiment where the interfering waves are two spatially separated components of the de Broglie wave of single 1.3 MeV hydrogen atoms formed close to either target nucleus in H++H2 electron-transfer collisions. Quantum interference strongly influences the results even though the hydrogen atoms have a de Broglie wavelength, lambda_{dB}, as small as 25 fm.

Electron capture induced dissociation of nucleotide anions in water nanodroplets.

We have studied the outcome of collisions between the hydrated nucleotide anion adenosine 5'-monophosphate (AMP) and sodium. Electron capture leads to hydrogen loss as well as water evaporation regardless of the initial number m of water molecules attached to the parent ion (m< or =16). The yield of dianions with microsecond lifetimes increases strongly with m, which is explained from dielectric screening of the two charges by the water nanodroplet. For comparison, collision induced dissociation results in water losses with no or very little damage of the AMP molecule itself.

Influence of treatment modality on angiographic outcome after coronary stenting in diabetic patients: a controlled study.

OBJECTIVES: This retrospective study was designed to determine the six-month angiographic outcome after stenting of native coronary arteries in insulin-treated (ITDM) and non-ITDM patients with diabetes mellitus (DM) and compare the results with those in non-DM patients. BACKGROUND: The influence of the treatment modality for DM on restenosis in patients undergoing coronary artery stenting has not been elucidated sufficiently. METHODS: A total of 1,439 (70%) of 2,061 patients underwent repeated angiography within six months of coronary stenting. The ITDM and non-ITDM (oral hypoglycemic drugs or diet) were documented in 48 (3.3%) and 177 patients (12.3%), respectively, leaving 1,214 non-DM patients. RESULTS: Baseline reference vessel diameter tended to be smaller in ITDM patients (mean, 2.73 mm) than in non-DM and non-ITDM patients (2.88 mm and 2.85 mm, respectively). However, percent diameter stenosis was not different. The median number of stents deployed was 1; median stent length was 15 mm. Statistically significant differences were present after stenting for the means of minimal lumen diameter (MLD) and acute gain between ITDM patients (MLD: 2.67 mm, acute gain: 1.98 mm) and non-DM patients (MLD: 2.81 mm, acute gain: 2.16 mm). At follow-up, percent diameter stenosis, late lumen loss and loss index were significantly higher in both non-ITDM lesions (42%, 1.14 mm and 0.56, respectively) and ITDM lesions (48%, 1.26 mm and 0.65, respectively) than in non-DM lesions (35%, 0.96 mm and 0.45, respectively). The corresponding differences between non-ITDM and ITDM lesions did not reach statistical significance. Restenosis rates in non-DM, non-ITDM and ITDM lesions were 23.8%, 32.8% (p = 0.013 vs. non-DM) and 39.6% (p = 0.02 vs. non-DM, p = 0.477 vs. non-ITDM), respectively. CONCLUSIONS: This study showed that compared with stenting in non-DM patients, stenting of native coronary arteries in DM patients is associated with significantly increased lumen renarrowing, regardless of the treatment modality for DM.

The role of cell adhesion molecules in Drosophila heart morphogenesis: faint sausage, shotgun/DE-cadherin, and laminin A are required for discrete stages in heart development.

Heart development in the Drosophila embryo starts with the specification of cardiac precursors from the dorsal edge of the mesoderm through signaling from the epidermis. Cardioblasts then become aligned in a single row of cells that migrate dorsally. After contacting their contralateral counterparts, cardioblasts undergo a cytoskeletal rearrangement and form a lumen. Its simple architecture and cellular composition makes the heart a good system to study mesodermal patterning, intergerm layer signaling, and the function of cell adhesion molecules (CAMs) during morphogenesis. In this paper we focus on three adhesion molecules, faint sausage (fas), shotgun/DE-cadherin (shg/DE-Cad), and laminin A (lam A), that are essential for heart development. fas encodes an Ig-like CAM and is required for the correct number of cardioblasts to become specified, as well as proper alignment of cardioblasts. shg/DE-Cad is expressed and required at a later stage than fas; in embryos lacking this gene, cardioblasts are specified normally and become aligned, but do not form a lumen. Additionally, cardioblasts of shg mutant embryos show a redistribution of phosphotyrosine as well as a loss of Armadillo from the membrane, indicating defects in cell polarity. The shg phenotype could be phenocopied by applying EGTA or cytochalasin D, supporting the view that Ca2+-dependent adhesion and the actin cytoskeleton are instrumental for heart lumen formation. As opposed to cell-cell adhesion, cell-substrate adhesion mechanisms are not required for heart morphogenesis, but only for maintenance of the differentiated heart. Embryos lacking the lam A gene initially developed a normal heart, but showed twists and breaks of cardioblasts at late embryonic stages. We discuss our findings in light of recent results that elucidate the function of different adhesion systems in vertebrate heart development.

Lifelong administration of high doses of ibandronate increases bone mass and maintains bone quality of lumbar vertebrae in rats.

As part of a long-term safety study the bisphosphonate ibandronate was investigated for its effects on bone quality in lumbar vertebrae in rats. Bone area, bone density and mechanical properties were assessed by peripheral quantitative computed tomography (pQCT), dual-energy X-ray absorptiometry (DXA) and compression tests. Female and male groups of Wistar rats received either vehicle or 3, 7 or 15 mg/kg per day of ibandronate over 104 weeks orally by gavage. Compared with the control group, bone mineral density, compressive strength and stiffness were significantly higher in ibandronate-treated animals, whereas no changes occurred in strain or modulus of elasticity. The increase in vertebral body stress was significant in some of the ibandronate-treated groups. The changes in mechanical properties appear to be due mainly to an increase in bone mass. A highly significant correlation was found between bone mineral density measured either by DXA (r = 0.86) or pQCT (r = 0.85) and maximal strength in vertebral bodies (p < 0.0001 each). In conclusion, we demonstrated that lifelong administration of doses of ibandronate far in excess of any therapeutically intended dose not only increases bone mass and apparent density, but also maintains or even slightly improves bone quality. Bone mineral density measured either by pQCT or DXA can be used as a predictor for ultimate strength in rat lumbar vertebral bodies after treatment with ibandronate.