Crystal structure of an aminoglycoside 6′-N-acetyltransferase: defining the GCN5-related N-acetyltransferase superfamily fold

AbstractBackground: The predominant mechanism of antibiotic resistance employed by pathogenic bacteria against the clinically used aminoglycosides is chemical modification of the drug. The detoxification reactions are catalyzed by enzymes that promote either the phosphorylation, adenylation or acetylation of aminoglycosides. Structural studies of these aminoglycoside-modifying enzymes may assist in the development of therapeutic agents that could circumvent antibiotic resistance. In addition, such studies may shed light on the development of antibiotic resistance and the evolution of different enzyme classes.Results: The crystal structure of the aminoglycoside-modifying enzyme aminoglycoside 6′-N-acetyltransferase type Ii (AAC(6′)-Ii) in complex with the cofactor acetyl coenzyme A has been determined at 2.7 Å resolution. The structure establishes that this acetyltransferase belongs to the GCN5-related N-acetyltransferase superfamily, which includes such enzymes as the histone acetyltransferases GCN5 and Hat1.Conclusions: Comparison of the AAC(6′)-Ii structure with the crystal structures of two other members of this superfamily, Serratia marcescens aminoglycoside 3-N-acetyltransferase and yeast histone acetyltransferase Hat1, reveals that of the 84 residues that are structurally similar, only three are conserved and none can be implicated as catalytic residues. Despite the negligible sequence identity, functional studies show that AAC(6′)-Ii possesses protein acetylation activity. Thus, AAC(6′)-Ii is both a structural and functional homolog of the GCN5-related histone acetyltransferases

Complex SCN8A DNA-abnormalities in an individual with therapy resistant absence epilepsy

Background De novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathy. We described a person with epileptic encephalopathy associated with a mosaic deletion of the SCN8A gene. Methods Array comparative genome hybridization was used to identify chromosomal abnormalities. Next Generation Sequencing was used to screen for variants in known and candidate epilepsy genes. A single nucleotide polymorphism array was used to test whether the SCN8A variants were in cis or in trans. Results We identified a de novo mosaic deletion of exons 2–14 of SCN8A, and a rare maternally inherited missense variant on the other allele in a woman presenting with absence seizures, challenging behavior, intellectual disability and QRS-fragmentation on the ECG. We also found a variant in SCN5A. Conclusions The combination of a rare missense variant with a de novo mosaic deletion of a large part of the SCN8A gene suggests that other possible mechanisms for SCN8A mutations may cause epilepsy; loss of function, genetic modifiers and cellular interference may play a role. This case expands the phenotype associated with SCN8A mutations, with absence epilepsy and regression in language and memory skills

Absence of the Transition into Abrikosov Vortex State of Two-Dimensional Type-II Superconductor with Weak Pinning

The resistive properties of thin amorphous NbO_{x} films with weak pinning were investigated experimentally above and below the second critical field H_{c2}. As opposed to bulk type II superconductors with weak pinning where a sharp change of resistive properties at the transition into the Abrikosov state is observed at H_{c4}, some percent below H_{c2} (V.A.Marchenko and A.V.Nikulov, 1981), no qualitative change of resistive properties is observed down to a very low magnetic field, H_{c4} < 0.006 H_{c2}, in thin films with weak pinning. The smooth dependencies of the resistivity observed in these films can be described by paraconductivity theory both above and below H_{c2}. This means that the fluctuation superconducting state without phase coherence remains appreciably below H_{c2} in the two-dimensional superconductor with weak pinning. The difference the H_{c4}/H_{c2} values, i.e. position of the transition into the Abrikosov state, in three- and two-dimensional superconductors conforms to the Maki-Takayama result 1971 year according to which the Abrikosov solution 1957 year is valid only for a superconductor with finite dimensions. Because of the fluctuation this solution obtained in the mean field approximation is not valid in a relatively narrow region below H_{c2} for bulk superconductors with real dimensions and much below H_{c2} for thin films with real dimensions. The superconducting state without phase coherence should not be identified with the mythical vortex liquid because the vortex, as a singularity in superconducting state with phase coherence, can not exist without phase coherence.Comment: 4 pages, 4 figure

Symptomatology of carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy

OBJECTIVE: To ascertain whether adverse effects experienced by people taking carbamazepine or oxcarbazepine could be attributed to carbamazepine- or oxcarbazepine-induced hyponatremia (COIH). METHODS: We performed an observational study, collecting data between 2017 and 2019 on serum sodium levels and adverse effects retrospectively in people with epilepsy while receiving treatment with either carbamazepine (CBZ) or oxcarbazepine (OXC). We defined hyponatremia as sodium level ≤134 mEq/L and severe hyponatremia as sodium level ≤128 mEq/L. Adverse effects experienced were compared between groups of individuals with and without hyponatremia. RESULTS: A total of 1370 people using CBZ or OXC were identified, of whom 410 had at least one episode of hyponatremia. We checked for symptoms related to the use of CBZ and OXC in 710 people (410 with and 300 without hyponatremia) and found relevant information in 688. Adverse effects occurred in 65% of people with hyponatremia compared to 21% with normal sodium levels (odds ratio [OR] 7.5, P ≤ .001) and in 83% of people with severe hyponatremia compared to 55% in those with mild hyponatremia (P ≤ .001). Significant predictors of adverse effects were the drug (OXC vs CBZ), and the number of concomitant anti-seizure medications. Dizziness (28% vs 6%), tiredness (22% vs 7%), instability (19% vs 3%), and diplopia (16% vs 4%) were reported more often in the hyponatremia group than in patients with normal levels. SIGNIFICANCE: People with COIH had a 7-fold increased risk of developing adverse effects during treatment. Clinicians should consider ascertainment of sodium levels in patients taking CBZ and OXC and act upon findings

Vortices in a Thin Film Superconductor with a Spherical Geometry

We report results from Monte Carlo simulations of a thin film superconductor in a spherical geometry within the lowest Landau level approximation. We observe the absence of a phase transition to a low temperature vortex solid phase with these boundary conditions; the system remains in the vortex liquid phase for all accessible temperatures. The correlation lengths are measured for phase coherence and density modulation. Both lengths display identical temperature dependences, with an asymptotic scaling form consistent with a continuous zero temperature transition. This contrasts with the first order freezing transition which is seen in the alternative quasi-periodic boundary conditions. The high temperature perturbation theory and the ground states of the spherical system suggest that the thermodynamic limit of the spherical geometry is the same as that on the flat plane. We discuss the advantages and drawbacks of simulations with different geometries, and compare with current experimental conclusions. The effect of having a large scale inhomogeneity in the applied field is also considered.Comment: This replacment contains substantial revisions: the new article is twice as long with new and different results on the thermodynamic limit on the sphere plus a full discussion on the alternative boundary conditions used in simulations in the LLL approximation. 19 pages, 12 encapsulated PostScript figures, 1 JPEG figure, uses RevTeX (with epsf

Characterization of human mesenchymal stem cells from Ewing sarcoma patients. Pathogenetic implications

Ewing Sarcoma (EWS) is a mesenchymal-derived tumor that generally arises in bone and soft tissue. Intensive research regarding the pathogenesis of EWS has been insufficient to pinpoint the early events of Ewing sarcomagenesis. However, the Mesenchymal Stem Cell (MSC) is currently accepted as the most probable cell of origin

Melting of two dimensional solids on disordered substrate

We study 2D solids with weak substrate disorder, using Coulomb gas renormalisation. The melting transition is found to be replaced by a sharp crossover between a high $T$ liquid with thermally induced dislocations, and a low $T$ glassy regime with disorder induced dislocations at scales larger than $\xi_{d}$ which we compute ($\xi_{d}\gg R_{c}\sim R_{a}$, the Larkin and translational correlation lengths). We discuss experimental consequences, reminiscent of melting, such as size effects in vortex flow and AC response in superconducting films.Comment: 4 pages, uses RevTeX, Amssymb, multicol,eps

Self-organized current transport through low angle grain boundaries in YBa2_2Cu3_3O7−δ_{7-\delta} thin films, studied magnetometrically

The critical current density flowing across low angle grain boundaries in YBa$_2$Cu$_3$O$_{7-\delta}$ thin films has been studied magnetometrically. Films (200 nm thickness) were deposited on SrTiO$_3$ bicrystal substrates containing a single [001] tilt boundary, with angles of 2, 3, 5, and 7 degrees, and the films were patterned into rings. Their magnetic moments were measured in applied magnetic fields up to 30 kOe at temperatures of 5 - 95 K; current densities of rings with or without grain boundaries were obtained from a modified critical state model. For rings containing 5 and 7 degree boundaries, the magnetic response depends strongly on the field history, which arises in large part from self-field effects acting on the grain boundary.Comment: 8 pages, including 7 figure

Is there a Phase Transition to the Flux Lattice State?

The sharp drops in the resistance and magnetization which are usually attributed to a phase transition from the vortex liquid state to a crystal state are explained instead as a crossover between three and two dimensional behavior, which occurs when the phase coherence length in the liquid becomes comparable to the sample thickness. Estimates of the width of the crossover region and the phase coherence length scales are in agreement with experiment.Comment: 4 pages, RevTe

Collective Mie Exciton-Polaritons in an Atomically Thin Semiconductor

Optically induced Mie resonances in dielectric nanoantennas feature low dissipative losses and large resonant enhancement of both electric and magnetic fields. They offer an alternative platform to plasmonic resonances to study light-matter interactions from the weak to the strong coupling regimes. Here, we experimentally demonstrate the strong coupling of bright excitons in monolayer WS$_2$ with Mie surface lattice resonances (Mie-SLRs). We resolve both electric and magnetic Mie-SLRs of a Si nanoparticle array in angular dispersion measurements. At the zero detuning condition, the dispersion of electric Mie-SLRs (e-SLRs) exhibits a clear anti-crossing and a Rabi-splitting of 32 meV between the upper and lower polariton bands. The magnetic Mie-SLRs (m-SLRs) nearly cross the energy band of excitons. These results suggest that the field of m-SLRs is dominated by out-of-plane components that do not efficiently couple with the in-plane excitonic dipoles of the monolayer WS$_2$. In contrast, e-SLRs in dielectric nanoparticle arrays with relatively high quality factors (Q $\sim$ 120) facilitate the formation of collective Mie exciton-polaritons, and may allow the development of novel polaritonic devices which can tailor the optoelectronic properties of atomically thin two-dimensional semiconductors.Comment: 27 pages, 7 figure