Live Birth of a Healthy Child in a Couple with Identical mtDNA Carrying a Pathogenic c.471_477delTTTAAAAinsG Variant in the MOCS2 Gene.

Molybdenum cofactor deficiency type B (MOCODB; #252160) is an autosomal recessive metabolic disorder that has only been described in 37 affected patients. In this report, we describe the presence of an in-frame homozygous variant (c.471_477delTTTAAAAinsG) in the MOCS2 gene in an affected child, diagnosed with Ohtahara syndrome according to the clinical manifestations. The analysis of the three-dimensional structure of the protein and the amino acid substitutions suggested the pathogenicity of this mutation. To prevent transmitting this mutation to the next generation, we used preimplantation genetic testing for the monogenic disorders (PGT-M) protocol to select MOCS2 gene mutant-free embryos for transfer in an in vitro fertilization (IVF) program. As a result, a healthy child was born. Interestingly, both parents of the proband shared an identical mitochondrial (mt) DNA control region, assuming their close relationship and thus suggesting that both copies of the nuclear rare variant c.471_477delTTTAAAAinsG may have been transmitted from the same female ancestor. Our estimation of the a priori probability of meeting individuals with the same mtDNA haplotype confirms the assumption of a possible distant maternal relationship among the proband's direct relatives.

Multimode Design and Piezoelectric Substrate Anisotropy Use to Improve Performance of Acoustic Liquid Sensors.

Using acoustic wave modes propagation in piezoelectric plates loaded with conductive liquids, peculiarities of the mode-liquid acoustoelectric interaction are studied. It is found that (i) in contrast to bulk and surface acoustic waves propagating in piezoelectric semiconductors, the acoustoelectric attenuation of the modes is not symmetric in respect to its maximum, (ii) a large increase in attenuation may be accompanied by a small decrease in phase velocity and vice versa, (iii) the peculiarities are valid for "pure" (without beam steering) and "not pure" (with beam steering) modes, as well as for modes of different orders and polarizations, and (iv) conductivity of test liquid increases electromagnetic leakage between input and output transducers, affecting results of the measurements. To decrease the leakage, the liquid should be localized between transducers, outside the zone over them. If so, the mode sensitivity may be as large as 8.6 dB/(S/m) for amplitude and 107°/(S/m) for phase. However, because of comparable cross-sensitivity towards viscosity and dielectric permittivity, modes with selective detection of liquid conductivity are not found.

Features of Neural Network Formation and Their Functions in Primary Hippocampal Cultures in the Context of Chronic TrkB Receptor System Influence.

Discovering the mechanisms underlying homeostatic regulation in brain neural network formation and stability processes is one of the most urgent tasks in modern neuroscience. Brain-derived neurotrophic factor (BDNF) and the tropomyosin-related kinase B (TrkB) receptor system have long been considered the main regulators of neuronal survival and differentiation. The elucidation of methods for studying neural network activity makes investigating the complex mechanisms underlying neural network structure reorganization during development and detecting new mechanisms for neuronal activity remodeling possible. In this in vitro study, we investigated the effects of chronic BDNF (the main TrkB stimulator) and ANA-12 (a TrkB receptor system blocker) administration on the formation of neural-glial networks. The formation of spontaneous bioelectrical activity and functional neural structure depend on TrkB receptors, and blocking TrkB receptors inhibits full bioelectrical activity development. Cross-correlation analysis demonstrated the decisive role of TrkB in the formation and "strengths" of activity centers. Even though an appropriate ANA-12 concentration is non-toxic to nerve cells, numerous cells in culture medium containing this reagent do not exhibit metabolic activity and are not functionally involved in signal transmission processes. Electron microscopy studies revealed that chronically influencing the TrkB receptor system significantly alters synaptic and mitochondrial apparatus capture in cells, and functional analysis of mitochondrial activity confirmed these findings. Because knowledge of interactions between TrkB-mediated regulation and the mitochondrial state under normal conditions is rather limited, data on these relationships are particularly interesting and require further investigation. Thus, we assume that the molecular cascades mediated by TrkB actively participate in the formation of functionally complete brain neural networks.

Propagation of the Anisimkin Jr.' and quasi-longitudinal acoustic plate modes in low-symmetry crystals of arbitrary orientation.

The Anisimkin Jr. (AN) acoustic plate mode having dominant and depth-independent longitudinal displacement (u(1) >> u(2), u(3); u(1) ≈ constant) is numerically found in tetragonal 4mm Li(2)B(4)O(7) crystal with one of the low-symmetry orientations (Euler angles 89°, 37°, 104°), as an example. The quasi-longitudinal (QL) modes with dominant and depth-dependent longitudinal displacement (u(1) >> u(2), u(3); u(1) ≠ constant) are experimentally detected along several propagation directions Θ in 128°y-LiNbO(3) plate, where Θ = 0°, 30°, 60°, and 90° with respect to the x-axis. Compared with more symmetrical plate materials and orientations, the displacement profiles of the AN and QL modes in lower-symmetry counterparts are qualitatively the same, but their phase profiles are more complicated. Moreover, like any acoustic wave, all plate modes in anisotropic crystals suffer from beam steering, in general. The power flow angles of the modes propagating in a fixed direction are different and depend on the mode order n.

Acoustic properties of the film/plate layered structure.

A new propagation medium-a layered structure composed of a film and a plate-is suggested and studied, using c-oriented ZnO and AlN films on (001), {100}-Si plate, as two opposite examples of slow-on-fast and fast-on-slow material combinations. For both structures, the modes belonging to Lamb, quasi-longitudinal (QL), and Anisimkin Jr.' (AN) families are found. For each family, the velocities v(n), displacement profiles, and electromechanical coupling coefficients K(n)2 for 4 electrode configurations are numerically calculated by the matrix method as a function of the mode order n = 0 to 8, plate thickness H/λ = 0 to 2.0, and film thickness h/λ = 0.02 to 0.04 (H and h are thicknesses; λ is the wavelength). Some high-order modes in the structure have K(n)2 = 0 for any H/λ, h/λ, and electrode configuration. Other modes possess variable K(n) 2 with a maximum value larger than the coupling coefficient for the Rayleigh SAWs in ZnO and AlN single crystals or layered structures using the same films and semi-infinite silicon substrate. There are also QL-modes having high velocity v(n), large K(n)2, and low propagation loss caused by liquid loading. These modes are well suited for liquid sensors.

The -112G>A polymorphism of the secretoglobin 3A2 (SCGB3A2) gene encoding uteroglobin-related protein 1 (UGRP1) increases risk for the development of Graves' disease in subsets of patients with elevated levels of immunoglobulin E.

The human secretoglobin 3A2 (SCGB3A2) gene encoding secretory uteroglobin-related protein 1 (UGRP1) resides on the chromosome region 5q31-33 that harbors a susceptibility locus to several autoimmune and inflammatory diseases, including asthma and Graves' disease (GD). Recently, association between the marker rs1368408 (-112G >A), located in the promoter region of the SCGB3A2 gene, and susceptibility to GD was found in Chinese and UK Caucasians. The study aim was to evaluate whether this polymorphism confers GD susceptibility in a large population cohort comprising 1,474 Russian GD patients and 1,619 controls. The marker rs1368408 was studied using a TaqMan allele discrimination assay. Serum levels of UGRP1 and immunoglobulin E (IgE) were assessed using enzyme-linked immunosorbent assay (ELISA) analyses. Association between the allele A of SCGB3A2 and a higher risk of GD (odds ratio [OR] = 1.33, P = 2.9 × 10(-5)) was shown. Both affected and non-affected carriers of the higher risk genotype A/A had significantly decreased levels of serum UGRP1 compared to the subjects homozygous for G/G (93 ± 37 pg/ml vs. 132 ± 45 pg/ml, P = 0.0011 for GD patients; 77 ± 28 pg/ml vs. 119 ± 33 pg/ml, P = 0.0019 for controls). Serum IgE levels were significantly higher in non-affected subjects homozygous for A/A compared to control individuals homozygous for G/G (153 ± 46 IU/ml vs. 122 ± 40 IU/ml, P = 0.0095). Our data suggest that the carriage of the SCGB3A2 -112A/A variant increases the risk for GD in subsets of patients with elevated levels of IgE, a hallmark of allergic asthma. Therefore, the SCGB3A2 -112G >A polymorphism may be considered as a likely marker linking susceptibility to allergy/asthma and GD on chromosome 5q31-33.

Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)-induced interferon-ß production in peripheral blood mononuclear cells of type 1 diabetes patients.

Melanoma differentiation-associated 5 (MDA5), a product of the IFIH1 gene, is responsible for sensing double-stranded viral double-stranded RNA (RNA). In this study, we showed a significant association of two rare IFIH1 variants, rs35744605 (E627X) and rs35667974 (I923V), with decreased risk of type 1 diabetes (T1D) in a Russian population (for the allele X627, odds ratio [OR] = 0.39, 95% confidence interval [95% CI] = 0.22-0.69, p = 0.0015; for the allele V923, OR = 0.45, 95% CI, 0.30-0.66, p = 5.4 × 10(-5)). We detected a 3.5-fold greater frequency of enteroviral RNA in T1D subjects compared with controls (p <1.0 × 10(-8)), and 2.1-fold more frequent presence of viral RNA in T1D patients with a recent-onset diabetes (duration ≤1 year) compared with those with a longer disease (p <1.0 × 10(-8)). The carriage of the predisposing IFIH1 EI/EI haplogenotype was significantly associated with a 1.5- to 1.7-fold increase in the poly(I:C)-stimulated secretion of IFN-ß in PMBCs compared with the other IFIH1 variants. The upregulated MDA5-dependent production of inflammatory cytokines could enhance the autoimmune destruction of ß-cells mediated by self-reactive T-cells.

Zn(2+)-transporter-8: a dual role in diabetes.

Diabetes mellitus arises from defects in insulin secretion or action, or both. In pancreatic islets, insulin production is linked with zinc transport mediated by zinc transporter ZnT-8, a product of the SLC30A8 gene. Therefore, altered activity of ZnT-8 is expected to be associated with impaired glucose-induced insulin response and promote progression from glucose intolerance to diabetes. Recent findings do emerge with a role of SLC30A8 in diabetes. Genome-wide association scans for type 2 diabetes (T2D) susceptibility loci revealed and then replicated a highly significant association between the R allele of the R325W variant of SLC30A8 (marker rs13266634) and susceptibility to T2D in Caucasians. A role of ZnT-8 as a new major self-antigenic determinant in type 1 diabetes (T1D) was found. Marker rs13266634 was also shown to modulate anti-ZnT-8 self-antibody specificity in islet autoimmunity. Hence, these findings suggest for a dual role of SLC30A8 in diabetes, which is consisted in conferring genetic susceptibility to T2D and being a major islet self-antigen in T1D as well. Here we characterize an emerging role of ZnT-8 in diabetes and discuss potential mechanisms of its involvement in the etiology of both forms of diabetes.

Ligase IV syndrome.

Ligase IV (LIG4) syndrome belongs to the group of hereditary disorders associated with impaired DNA damage response mechanisms. Subjects affected with this rare autosomal recessive disease exhibit microcephaly, unusual facial features, growth retardation, developmental delay, skin anomalies, and are typically pancytopenic. The disease is characterized by pronounced radiosensitivity, genome instability, malignancy, immunodeficiency, and bone marrow abnormalities. LIG4 syndrome results from mutations in the DNA ligase IV gene encoding an enzyme that plays a pivotal role in repairing double strand DNA breaks and V(D)J recombination. Since LIG4 null-mutant mice are embryonic lethal and biallelic null mutations have not been described to date in LIG4-deficient patients, viability of the DNA ligase IV deficiency syndrome appears to require at least one allele with a hypomorphic mutation. Mutations R278H, Q280R, H282L, M249E located in the vicinity of the active site are typical hypomorphic because they do not affect ligase expression and retain residual albeit reduced activity of the enzyme at levels of 5-10% of that for the wild-type ligase. Carriers heterozygous for those mutations usually develop moderate defects in V(D)J recombination, mild immune abnormalities and malignancy. In contrast, mutations resided in OBD, i.e. in the C-terminal subdomain of the catalytic domain, and in XRCC4-binding domain more dramatically inhibit the ligase function and also greatly decrease its expression. A truncating mutation R580X and a frameshift mutation K424FS resulting in loss of the C-terminal XRCC4-binding domain have deleterious effect on both expression and function of LIG4 and represent a null allele.

Genetic variations in DNA repair genes, radiosensitivity to cancer and susceptibility to acute tissue reactions in radiotherapy-treated cancer patients.

Ionizing radiation is a well established carcinogen for human cells. At low doses, radiation exposure mainly results in generation of double strand breaks (DSBs). Radiation-related DSBs could be directly linked to the formation of chromosomal rearrangements as has been proven for radiation-induced thyroid tumors. Repair of DSBs presumably involves two main pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). A number of known inherited syndromes, such as ataxia telangiectasia, ataxia-telangiectasia like-disorder, radiosensitive severe combined immunodeficiency, Nijmegen breakage syndrome, and LIG4 deficiency are associated with increased radiosensitivity and/or cancer risk. Many of them are caused by mutations in DNA repair genes. Recent studies also suggest that variations in the DNA repair capacity in the general population may influence cancer susceptibility. In this paper, we summarize the current status of DNA repair proteins as potential targets for radiation-induced cancer risk. We will focus on genetic alterations in genes involved in HR- and NHEJ-mediated repair of DSBs, which could influence predisposition to radiation-related cancer and thereby explain interindividual differences in radiosensitivity or radioresistance in a general population.

The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies.

Interleukin-2 (IL-2) plays an established role in T-cell regulation through binding to the high-affinity IL-2 receptor (IL-2R). The alpha-chain encoded by the IL2RA (CD25) gene is a substantial component of the high-affinity receptor molecule highly expressed by activated T lymphocytes. Recently, a strong evidence was obtained for the involvement of IL-2RA in conferring susceptibility to type 1 diabetes (T1D). Significant association with T1D was also found in the region on chromosome 4q27 containing the IL2 gene and homologous to the susceptibility locus idd3 in non-obese diabetic (NOD) mice, an animal model for human T1D. Here we focus on the discussion of these new findings suggesting for a crucial role of IL-2/IL-2RA-mediated regulatory mechanisms in preventing T1D. The non-redundant role of IL-2 and its receptor in etiology of T1D could be particularly attributable to the regulation of CD4+ CD25+ regulatory T cells, whose function is critical in maintaining immune homeostasis.