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This review is devoted to a comprehensive analysis of DNA copy number variations (CNVs) identified in patients with neurodevelopmental disorders (NDDs) from the literature. The selection of publications was conducted using specifically developed criteria. CNVs were characterized based on their clinical significance, type of copy number alteration (microdeletion/microduplication), size, origin, and gene content. The study sample comprised 3375 patients with NDDs. Pathogenic and likely pathogenic CNVs, as well as variants of uncertain clinical significance, were identified in 395 individuals (12%). Chromosomal variations of each category were identified in 89 (3%), 56 (2%), and 241 (7%) patients, respectively. Nine individuals exhibited combinations of CNVs with different clinical significance. The number of duplications slightly exceeded the number of deletions (250 and 204, respectively). The size of most CNVs ranged from 193 bp to 400 kb and from 1 to 3 Mb (237 and 96, respectively). Seventy-two variants originated de novo, while 165 were inherited. Eighty-six CNVs were associated with 33 known microdeletion/microduplication syndromes. The most prevalent syndromes were 1q21.1 duplication (7/395, 1.8%) (OMIM: 612475), 2p16.3 deletion (9/395, 2.3%) (OMIM: 614332), 15q13.3 deletion (7/395, 1.8%) (OMIM: 612001), 16p11.2 deletion (9/395, 2.3%) (OMIM: 611913), and 22q11.2 duplication (7/395, 1.8%) (OMIM: 608363) syndromes. Enrichment analysis revealed that pathogenic CNVs, as well as variants of uncertain clinical significance, are enriched in genes associated with abnormal behavioral and neurological phenotypes. Likely pathogenic CNVs included genes associated with disorders of the nervous system and homeostasis/metabolism. [ABSTRACT FROM AUTHOR]

A brief history of the development of ideas about pleiotropy, its types, and the overall prevalence of pleiotropic loci in the human genome, as well as pleiotropic variants and genes within the same group of pathologies (disorders of psychomotor development) and between different diseases are discussed. Data on the association of the birth of a child with intellectual disability in a woman with a history of miscarriage are presented. The involvement of the same copy number variations (CNVs) in disorders of prenatal and postnatal development has been shown. The hypothesis is proposed that these CNVs are pleiotropic and manifested by one pathology or another, depending on additional modifying factors. [ABSTRACT FROM AUTHOR]

This review concerns the mechanisms of bacterial cell survival based on the induction of hibernation factors (HFs) that suppress protein synthesis via the inhibition of ribosomal functions. These factors include ribosome-binding proteins that inhibit 70S ribosomes (RaiA), form their inactive 100S dimers (RMF and HPF), or act at different stages of the translation cycle (RsfS, YqjD, SRA, and EttA). In some cells of the population, HFs cause the formation of a dormant state, which is characterized by a low rate of metabolic processes. This results in the tolerance of these cells and, as a consequence, the ability to persist in the presence of antibiotics and under stress conditions. The role of metabolic factors (polyamines and indoles) in the regulation of the expression levels of hibernation genes is discussed. [ABSTRACT FROM AUTHOR]

Human ring chromosomes are often unstable during mitosis, and daughter cells can be partially or completely aneuploid. We studied the mitotic stability of four ring chromosomes, 8, 13, 18, and 22, in long-term cultures of skin fibroblasts and induced pluripotent stem cells (iPSCs) by GTG karyotyping and aCGH. Ring chromosome loss and secondary aberrations were observed in all fibroblast cultures except for r(18). We found monosomy, fragmentation, and translocation of indexed chromosomes. In iPSCs, aCGH revealed striking differences in mitotic stability both between iPSC lines with different rings and, in some cases, between cell lines with the same ring chromosome. We registered the spontaneous rescue of karyotype 46,XY,r(8) to 46,XY in all six iPSC lines through ring chromosome loss and intact homologue duplication with isoUPD(8)pat occurrence, as proven by SNP genotype distribution analysis. In iPSCs with other ring chromosomes, karyotype correction was not observed. Our results suggest that spontaneous correction of the karyotype with ring chromosomes in iPSCs is not universal and that pluripotency is compatible with a wide range of derivative karyotypes. We conclude that marked variability in the frequency of secondary rearrangements exists in both fibroblast and iPSC cultures, expanding the clinical significance of the constitutional ring chromosome. [ABSTRACT FROM AUTHOR]

Chromosomal microdeletion syndromes present with a wide spectrum of clinical phenotypes that depend on the size and gene content of the affected region. In a healthy carrier, epigenetic mechanisms may compensate for the same microdeletion, which may segregate through several generations without any clinical symptoms until the epigenetic modifications no longer function. We report 2 novel cases of Xq24 microdeletions inherited from mothers with extremely skewed X-chromosome inactivation (sXCI). The first case is a boy presenting with X-linked mental retardation, Nascimento type, due to a 168-kb Xq24 microdeletion involving 5 genes (CXorf56, UBE2A, NKRF, SEPT6, and MIR766) inherited from a healthy mother and grandmother with sXCI. In the second family, the presence of a 239-kb Xq24 microdeletion involving 3 additional genes (SLC25A43, SLC25A5-AS1, and SLC25A5) was detected in a woman with sXCI and a history of recurrent pregnancy loss with a maternal family history without reproductive wastages or products of conception. These cases provide evidence that women with an Xq24 microdeletion and sXCI may be at risk for having a child with intellectual disability or for experiencing a pregnancy loss due to the ontogenetic pleiotropy of a chromosomal microdeletion and its incomplete penetrance modified by sXCI. [ABSTRACT FROM AUTHOR]

Using chromosome microarray analysis, 52 samples of placental tissues from first trimester human spontaneous abortions were examined. One hundred twenty copy number variations (CNVs) were identified, affecting one or more genes (total of 427 genes). Using enrichment analysis with the mammalian phenotype ontology, all genes were divided into 183 categories (p ≤ 0.05). The embryogenesis category included 22 genes: AIP, BMP4, BMP5, CDKN1C, EXT1, GAB1, H19, HOXD13, IGF2, KIT, LDHA, NKX2-5, NRK, PEG3, PHLDA2, SMCHD1, SMN1, TBX3, TGIF1, TH, TLX2, and TRR. In this paper, the functions of each of the above genes and pathological phenotypes associated with mutations in them are discussed. A hypothesis of the pleiotropic effect of genes involved in CNVs in spontaneous abortions is proposed. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cells (iPSCs) are a promising source of cells for regenerative medicine, study of the pathogenesis of various diseases, screening of pharmacological drugs, and other clinical and basic research. However, the maintenance of the genetic stability of the cells during reprogramming, long-term culture, and directed differentiation is necessary for the use of iPSCs. Large chromosomal aberrations affect the quality of iPSCs most adversely, so the review focuses on the analysis of chromosomal abnormalities, including the recurrent aneuploidy; the sources of its origin, the effect of reprogramming, and long-term culture on the accumulation of chromosome aberrations are discussed. Cases of spontaneous correction of the iPSCs karyotype and the possibility of induced correction of the large chromosomal abnormalities by removing or silencing the extra homologue are considered. [ABSTRACT FROM AUTHOR]

Persisters are rare phenotypic variants of regular bacterial cells that survive lethal antibiotics or stresses owing to slowing down of their metabolism. Recently, we have shown that polyamine putrescine can upregulate persister cell formation in Escherichia coli via the stimulation of rpoS expression, encoding a master regulator of general stress response. We hypothesized that rmf and yqjD, the stationary-phase genes responsible for ribosome inactivation, might be good candidates for the similar role owing to their involvement in translational arrest and the ability to be affected by polyamines. Using reporter gene fusions or single and multiple knockout mutations in rpoS, rmf and yqjD genes, we show in this work that (i) E. coli polyamines spermidine and cadaverine can upregulate persistence, like putrescine; (ii) polyamine effects on persister cell formation are mediated through stimulation of expression of rpoS, rmf and yqjD genes; (iii) these genes are involved in persister cell formation sequentially in a dynamic fashion as cells enter the stationary phase. The data obtained in this work can be used to develop novel tools relying on a suppression of polyamine metabolism in bacteria to combat persister cells as an important cause of infections refractory to antibiotics. [ABSTRACT FROM AUTHOR]

The genomic architecture predisposed to the emergence of DNA copy number variation causing a new class of human chromosomal diseases-reciprocal microdeletion and microduplication syndromes- is reviewed in the paper. The molecular mechanisms of such chromosomal abnormalities are described. The problems of the interpretation of their clinical significance and genotype-phenotype correlations are discussed. The classification of phenotypes due to reciprocal chromosomal microdeletions and microduplications is shown. Published by 2015, reciprocal mutations associated with inherited and congenital human pathology and involving 58 chromosomal regions are summarized. [ABSTRACT FROM AUTHOR]

Background: Detection of submicroscopic chromosomal alterations in patients with a nonspecific intellectual disability (ID) allows significant improvement in delineation of the regions of the genome that are associated with brain development and function. However, these chromosomal regions usually contain several protein-coding genes and regulatory elements, complicating the understanding of genotype-phenotype correlations. We report two siblings with ID and an unrelated patient with atypical autism who had 3p26.3 microdeletions and one intellectually disabled patient with a 3p26.3 microduplication encompassing only the CNTN6 gene. Results: Two 295.1-kb microdeletions and one 766.1-kb microduplication of 3p26.3 involving a single gene, CNTN6, were identified with an Agilent 60 K array. Another 271.9-kb microdeletion of 3p26.3 was detected using an Affymetrix CytoScan HD chromosome microarray platform. The CHL1 and CNTN4 genes, although adjacent to the CNTN6 gene, were not affected in either of these patients. Conclusions: The protein encoded by CNTN6 is a member of the immunoglobulin superfamily and functions as a cell adhesion molecule that is involved in the formation of axon connections in the developing nervous system. Our results indicate that CNTN6 may be a candidate gene for ID. [ABSTRACT FROM AUTHOR]

Persisters are suggested to be the products of a phenotypic variability that are quasi-dormant forms of regular bacterial cells highly tolerant to antibiotics. Our previous investigations revealed that a decrease in antibiotic tolerance of Escherichia coli cells could be reached through the inhibition of key enzymes of polyamine synthesis (putrescine, spermidine). We therefore assumed that polyamines could be involved in persister cell formation. Data obtained in our experiments with the polyamine-deficient E. coli strain demonstrate that the formation of persisters tolerant to netilmicin is highly upregulated by putrescine in a concentration-dependent manner when cells enter the stationary phase. This period is also accompanied by dissociation of initially homogenous subpopulation of persister cells to some fractions differing in their levels of tolerance to netilmicin. With three independent experimental approaches, we demonstrate that putrescine-dependent upregulation of persister cell formation is mediated by stimulation of rpoS expression. Complementary activity of putrescine and RpoS results in ~ 1000-fold positive effect on persister cell formation. [ABSTRACT FROM AUTHOR]

Analysis of the prevalence of copy number variations of the CNTN6 gene, recently selected as a new candidate gene for intellectual disorders, was performed. Real-time PCR did not detect any change in the number of CNTN6 gene copies in a group of 200 patients with impaired intellectual development. However, taking into account our data from the previous aCGH analysis and published data, the overall frequency of microdeletions and microduplications of CNTN6 was estimated as 1: 265 (0.4%). The common phenotypic features of 40 patients with microdeletions and microduplications of CNTN6 appeared to be the autism spectrum disorders, developmental delay, intellectual disability, seizures, cognitive impairment, cardiological defects, and behavioral problems. [ABSTRACT FROM AUTHOR]

Abstract: The use of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated the identification of many new microdeletion/microduplication syndromes (MMSs). Furthermore, this method has allowed for the identification of copy number variations (CNVs) whose pathogenic role has yet to be uncovered. Here, we report on our application of array CGH for the identification of pathogenic CNVs in 79 Russian children with intellectual disability (ID). Twenty-six pathogenic or likely pathogenic changes in copy number were detected in 22 patients (28%): 8 CNVs corresponded to known MMSs, and 17 were not associated with previously described syndromes. In this report, we describe our findings and comment on genes potentially associated with ID that are located within the CNV regions. [Copyright &y& Elsevier]

The methylation profiles of the placental tissues of human embryos with normal karyotype and trisomy 16 were compared using an Infinium HumanMethylation27 BeadChip array (Illumina, United States). Numerous differences between the extraembryonic tissues with diploid and aneuploid karyotypes were observed. The extraembryonic mesoderm of embryos with trisomy 16 appeared to be less methylated than the diploid tissue, whereas the cytotrophoblast of aneuploid embryos was hypermethylated. The presence of the supernumerary chromosome was shown to influence the epigenetic profile of the genome by changing the level of methylation of CpG sites of all chromosomes. However, the largest number of differentially methylated loci was found on chromosome 16. Furthermore, more often, the epimutations were tissuespecific. In both tissues, the hypomethylated genes belong to the groups of genes responsible for different metabolic processes, whereas the hypermethylated genes control the processes of development, cell adhesion, immune response, and response to stimulus. [ABSTRACT FROM AUTHOR]

For the first time, DNA methylation patterns in the human cytotrophoblast and the extraembryonic mesoderm were determined using a genome-wide Infinium HumanMethylation27 BeadChip Array (Illumina, United States). These tissues are derivatives of the trophectoderm and the inner cell mass of the blastocyst and have substantial differences in the dynamics of epigenetic genome reprogramming during early stages of differentiation. It was shown that the genome of the extraembryonic mesoderm cells was more methylated than that of the cytotrophoblast, similarly to the findings in other mammalian species. There were differences in the methylation patterns of single CpG dinucleotides and dinucleotides located within promoter CpG islands: in both tissues most single CpG dinucleotides were methylated, promoters CpG island sites were not. A comparative analysis revealed 202 differentially methylated genes in the extraembryonic mesoderm and 40 such genes in the cytotrophoblast. These genes are responsible for a number of diverse biological processes. However, in the extraembryonic mesoderm, a majority of genes identified were responsible for DNA binding and transcriptional factor activity, whereas those identified in the cytotrophoblast were responsible for transport and protein and cytokine secretion. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms of cell cycle regulation providing for maintenance of genome stability and precise transmission of hereditary information to the daughter cells attract considerable interest. Up-to-date molecular technologies allow the genome-wide methylation pattern to be determined in a single experiment. In this work, we pioneered in determining the epigenetic status of the placental tissues of the human embryos with mosaic karyotype using a genome-wide Illumina Infinium HumanMethylation27 BeadChip array (Illumina, United States), comprising 27578 CpG dinucleotides contained in 14475 genes. The groups of genes associated with the cell cycle and its regulation that contain differentially methylated CpG sites in their promoter regions have been determined. It was demonstrated that the methylation level most frequently changed in oncogenes ( ARHGEF1 and FGF5), tumor suppressors ( APC2, BRACA2, DCC, GRLF1, RB1, TP73, TSPYL2, and VHL), and the genes involved in the regulation of chromosome segregation ( CNTROB, GMNN, PROCR, and TACC1). [ABSTRACT FROM AUTHOR]

The sex ratio and X-chromosome inactivation were analyzed in placental tissues of human spontaneous abortuses with pure and mosaic forms of chromosome 16 trisomy. The sex ratio value was found to decrease with an increase in the share of cells with the trisomic karyotype, which suggests differential survival of embryos belonging to different sexes. The pattern of X-chromosome inactivation in cells of extraembryonic mesoderm in the control group of embryos and in spontaneous abortuses with the level of trisomy 16 below 80% corresponded to random X-inactivation, whereas in most embryos with a frequency of trisomy 16 exceeding 80% skewed inactivation was observed. Our results support the hypothesis about the existence of an autosomal transfactor influencing the initiation of X-chromosome inactivation and suggest its possible localization on chromosome 16. [ABSTRACT FROM AUTHOR]

The methylation status of the promoter region of the cell cycle gene P14ARF was studied in the extraembryonic mesoderm and in the cytotrophoblast of 46 human spontaneous abortions with chromosomal mosaicism. Aberrant methylation of alleles of this gene was revealed for the first time in placental tissues of 9% of embryos. The identified epimutations were found to be characteristic of embryos with aneuploid cell clones of postzygotic origin. It is suggested that epigenetic inactivation of loci responsible for the regulation of cell division and for segregation of chromosomes is associated with the origin of mosaic forms of the karyotype at early stages of human embryonic development. [ABSTRACT FROM AUTHOR]

The methylation status of the cell cycle control gene RB1 has been studied in placental tissues of spontaneous abortions of the first trimester of pregnancy with mosaic variants of numerical chromosomal abnormalities verified by a molecular cytogenetic examination. Aberrant methylation of the gene promoter region has been revealed for the first time in 20% of embryos with chromosomal mosaicism that died in utero. A maximum frequency of epimutations was recorded in a group of embryos with a low level of abnormal cells for which mitotic errors are most likely to determine the formation of mosaic aneuploidy in primary euploid zygotes. It has been suggested that aberrant epigenetic genomic modifications at early stages of human embryonic development can be one of the mechanisms promoting genomic instability realized in the form of mosaic abnormalities of the karyotype that are incompatible with the normal course of embryogenesis. [ABSTRACT FROM AUTHOR]

Bacterial persistence coupled with biofilm formation is directly associated with failure of antibiotic treatment of tuberculosis. We have now identified 4-(4,7-DiMethyl-1,2,3,4-tetrahydroNaphthalene-1-yl)Pentanoic acid (DMNP), a synthetic diterpene analogue, as a lead compound that was capable of suppressing persistence and eradicating biofilms in Mycobacterium smegmatis. By using two reciprocal experimental approaches – Δ rel Msm and Δ relZ gene knockout mutations versus rel Msm and relZ overexpression technique – we showed that both Rel Msm and RelZ (p)ppGpp synthetases are plausible candidates for serving as targets for DMNP. In vitro , DMNP inhibited (p)ppGpp-synthesizing activity of purified Rel Msm in a concentration-dependent manner. These findings, supplemented by molecular docking simulation, suggest that DMNP targets the structural sites shared by Rel Msm , RelZ, and presumably by a few others as yet unidentified (p)ppGpp producers, thereby inhibiting persister cell formation and eradicating biofilms. Therefore, DMNP may serve as a promising lead for development of antimycobacterial drugs. [Display omitted] • DMNP is a synthetic diterpene analogue inhibiting mycobacterial persistence • (p)ppGpp is an essential cell regulator of persistence and biofilm formation • DMNP targets Rel Msm , RelZ (p)ppGpp synthetases and inhibits their activities • Lack of (p)ppGpp reduces cell survival by limiting persistence and biofilm formation Tkachenko et al. revealed that DMNP, a synthetic analogue of natural marine diterpene erogorgiaene, binds to the structurally similar sites of Rel Msm , RelZ, and presumably of some other as yet unidentified (p)ppGpp producers thereby inhibiting persister cell formation and eradicating biofilms. [ABSTRACT FROM AUTHOR]

The possibilities of single crystals synthesis in conditions of nonisotropic one-axis contraction were studied. As a result of the work the single crystals of the tetragonal polymerized phase of C60 without orientational domains were obtained. The crystal structure of this phase was resolved using single crystal x-ray diffraction data. A structural model of this phase proposed early was confirmed and refined to final R = 0.075. The structure is slightly disordered. It consists of a random combination of the P42/mmc layers (84%) and of the Immm layers (16%), along the c axis. [ABSTRACT FROM AUTHOR]

Dimerization kinetics was studied for fullerene C[sub 60] by IR spectroscopy at a pressure of 1.5 GPa in the temperature range 373–473 K. The kinetic curves for the formation of a dimer (C[sub 60])[sub 2] were obtained using its analytical IR band at 796cm[sup – 1]. Under the assumption that pressure-induced C[sub 60] dimerization is a second-order irreversible reaction, the reaction rate constants were determined at different temperatures. The corresponding activation energy and preexponential factor were found to be 134±6 kJ/mol and (1.74±0.24) ×10[sup 14]s[sup –1], respectively. The specific features of the solid-phase C[sub 60] dimerization in simple cubic and face-centered cubic fullerite phases are discussed. © 2000 MAIK “Nauka / Interperiodica”. [ABSTRACT FROM AUTHOR]

The dimerization of C[sub 60] fullerene under conditions of quasi-hydrostatic compression at temperatures above 293 K is investigated by IR spectroscopy, Raman scattering (RS) spectroscopy, and x-ray diffraction. The measured dimer (C[sub 60])[sub 2] content in the products of the polymerization of fullerite as a function of the pressure, temperature, and treatment time shows that dimerization occurs even at room temperature in the entire pressure range above ∼1.0 GPa. However, at least at temperatures above 400 K dimerization does not result in the formation of a dimer phase as a stable modification of the system, since the dimer is an intermediate product of the transformation. It is shown that increasing the holding time at 423 K decreases the content of the dimer fraction in the samples and results in the formation of linear (at 1.5 GPa) and two-dimensional (at 6.0 GPa) polymers, which are structure-forming elements of the orthorhombic and rhombohedral polymerized phases. © 1998 American Institute of Physics. [ABSTRACT FROM AUTHOR]

It is established by x-ray diffraction and Raman scattering that the polymerization of C[sub 60] fullerene at 1.5 GPa and 723 K leads to the formation of an orthorhombic phase that is different from the previously identified high-pressure orthorhombic phase. It is determined by a calculation of the optimal packing of linear C[sub 60] polymers by the method of atom-atom potentials that the energetically favorable structure of the orthorhombic phase belongs to the space group Pnnm and not the previously proposed group Immm. The computed value of the rotation angle of the polymer chains that corresponds to the minimum packing energy was equal to 61°. The mechanisms leading to the formation of the polymerized phases are discussed on the basis of the results obtained. [ABSTRACT FROM AUTHOR]

Modifications of carbon which are formed from C60 fullerite at pressures up to 10.0 GPa and temperatures up to 1900 K are studied by x-ray diffraction, Raman spectroscopy, and atomic force microscopy methods. The pressures p and temperatures T at which atomic, molecular, and polymolecular structures form under conditions of quasihydrostatic compression are determined. It is shown that, together with polymerization, another type of chemical interaction of the molecules, called polycondensation, which leads to the formation of polymolecular structures with a shortest intermolecular distance of 0.65 nm, is possible in the system. Three-dimensional polycondensation of C60 fullerene is explained by the special properties of the new carbon states. © 1996 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Ring chromosome 8 (r(8)) is one of the least frequent ring chromosomes. Usually, maternal chromosome 8 forms a ring, which can be lost from cells due to mitotic instability. The 8q24 region contains the imprinted KCNK9 gene, which is expressed from the maternal allele. Heterozygous KCNK9 mutations are associated with the imprinting disorder Birk-Barel syndrome. Here, we report a 2.5-year-old boy with developmental delay, microcephaly, dysmorphic features, diffuse muscle hypotonia, feeding problems, motor alalia and noncoarse neurogenic type of disturbance of muscle electrogenesis, partially overlapping with Birk-Barel syndrome phenotype. Cytogenetic analysis of lymphocytes revealed his karyotype to be 46,XY,r(8)(p23q24.3)[27]/45,XY,−8[3]. A de novo 7.9 Mb terminal 8p23.3p23.1 deletion, a 27.1 Mb 8p23.1p11.22 duplication, and a 4.4 Mb intact segment with a normal copy number located between them, as well as a 154-kb maternal LINGO2 gene deletion (9p21.2) with unknown clinical significance were identified by aCGH + SNP array. These aberrations were confirmed by real-time PCR. According to FISH analysis, the 8p23.1-p11.22 duplication was inverted. The ring chromosome originated from maternal chromosome 8. Targeted massive parallel sequencing did not reveal the KCNK9 mutations associated with Birk-Barel syndrome. Our data allow to assume that autosomal monosomy with inactive allele of imprinted gene arising from the loss of a ring chromosome in some somatic cells may be an etiological mechanism of mosaic imprinting disorders, presumably with less severe phenotype. [ABSTRACT FROM AUTHOR]

Skewed X-chromosome inactivation (sXCI) can be a marker of lethal genetic variants on the X chromosome in a woman since sXCI modifies the pathological phenotype. The aim of this study was to search for CNVs in women with miscarriages and sXCI. XCI was assayed using the classical method based on the amplification of highly polymorphic exon 1 of the androgen receptor (AR) gene. The XCI status was analysed in 313 women with pregnancy loss and in 87 spontaneously aborted embryos with 46,XX karyotype, as well as in control groups of 135 women without pregnancy loss and 64 embryos with 46,XX karyotype from induced abortions in women who terminated a normal pregnancy. The frequency of sXCI differed significantly between women with miscarriages and women without pregnancy losses (6.3% and 2.2%, respectively; p = 0.019). To exclude primary causes of sXCI, sequencing of the XIST and XACT genes was performed. The XIST and XACT gene sequencing revealed no known pathogenic variants that could lead to sXCI. Molecular karyotyping was performed using aCGH, followed by verification of X-linked CNVs by RT-PCR and MLPA. Microdeletions at Xp11.23 and Xq24 as well as gains of Xq28 were detected in women with sXCI and pregnancy loss. [ABSTRACT FROM AUTHOR]

The kinetics of fullerene solid-phase dimerization proceeding through the 2 + 2 cycloaddition of C[sub 60] at a pressure of 1.5 GPa is investigated by vibrational spectroscopy in the temperature range 373-473 K. Kinetic curves for the formation of (C[sub 60])[sub 2] dimers are obtained using the analytical band at 796 cm[sup -1] in the IR spectra of the (C[sub 60])[sub 2] dimer molecule. Under the assumption that the pressure-induced dimerization of C[sub 60] is an irreversible second-order reaction, the reaction rate constants are determined at different temperatures. The activation energy and the preexponential factor are found to be equal to 134 ± 6 kJ/mol and (1.74 ± 0.24) × 10[sup 14] s[sup -1], respectively. [ABSTRACT FROM AUTHOR]

Most copy number variations (CNVs) in the human genome display incomplete penetrance with unknown underlying mechanisms. One such mechanism may be epigenetic modification, particularly DNA methylation. The IMMP2L gene is located in a critical region for autism susceptibility on chromosome 7q (AUTS1). The level of DNA methylation was assessed by bisulfite sequencing of 87 CpG sites in the IMMP2L gene in 3 families with maternally inherited 7q31.1 microdeletions affecting the IMMP2L gene alone. Bisulfite sequencing revealed comparable levels of DNA methylation in the probands, healthy siblings without microdeletions, and their fathers. In contrast, a reduced DNA methylation index and increased IMMP2L expression were observed in lymphocytes from the healthy mothers compared with the probands. A number of genes were upregulated in the healthy mothers compared to controls and downregulated in probands compared to mothers. These genes were enriched in components of the ribosome and electron transport chain, as well as oxidative phosphorylation and various degenerative conditions. Differential expression in probands and mothers with IMMP2L deletions relative to controls may be due to compensatory processes in healthy mothers with IMMP2L deletions and disturbances of these processes in probands with intellectual disability. The results suggest a possible partial compensation for IMMP2L gene haploinsufficiency in healthy mothers with the 7q31.1 microdeletion by reducing the DNA methylation level. Differential DNA methylation of intragenic CpG sites may affect the phenotypic manifestation of CNVs and explain the incomplete penetrance of chromosomal microdeletions. [ABSTRACT FROM AUTHOR]

Differentiation of induced pluripotent stem cells (iPSCs) from patients and healthy donors allows in vitro study of genetic disorders. The authors have previously reported a clinical case of recurrent pregnancy loss in a patient with skewed X-chromosome inactivation in peripheral blood lymphocytes, endometrium, and buccal epithelium. A 239 kb microdeletion at Xq24 that affected eight genes, including UBE2A, has been found. In this work, an iPSC line iTAF15Xsk4 was produced from the patient's skin fibroblasts using nonintegrating episomal vectors. The iPSC line had a normal karyotype, expressed pluripotency markers, and expressed markers of all three germ layers upon differentiation in embryoid bodies. This cell line could be used for the UBE2A deficiency syndrome study. [ABSTRACT FROM AUTHOR]

Background: Ring chromosome instability may influence a patient's phenotype and challenge its interpretation. Results: Here, we report a 4-year-old girl with a compound phenotype. Cytogenetic analysis revealed her karyotype to be 46,XX,r(22). aCGH identified a 180 kb 22q13.32 duplication, a de novo 2.024 Mb subtelomeric 22q13.32-q13.33 deletion, which is associated with Phelan-McDermid syndrome, and a maternal single gene 382-kb TUSC7 deletion of uncertain clinical significance located in the region of the 3q13.31 deletion syndrome. All chromosomal aberrations were confirmed by real-time PCR in lymphocytes and detected in skin fibroblasts. The deletions were also found in the buccal epithelium. According to FISH analysis, 8% and 24% of the patient's lymphocytes and skin fibroblasts, respectively, had monosomy 22. Conclusions: We believe that a combination of 22q13.32-q13.33 deletion and monosomy 22 in a portion of cells can better define the clinical phenotype of the patient. Importantly, the in vivo presence of monosomic cells indicates ring chromosome instability, which may favor karyotype correction that is significant for the development of chromosomal therapy protocols. [ABSTRACT FROM AUTHOR]

Introduction: Genetic disorders underlie a significant number of cases of mental retardation (MR). However, the traditionally used routine karyotyping is not able to detect small but often clinically relevant aberrations. High-resolution genome-wide microarray technologies may help to increase the detectability of MR etiology. Objectives: To improve MR diagnostics. Aims: To identify the novel CNV regions and susceptibility genes in MR patients. Methods: Large chromosomal rearrangements, biochemical defects, and known monogenic syndromes accompanied by MR were ruled out for 71 patients. Further the genome-wide analysis using CGH Microarray Kits 4×44K and 8×60K (Agilent Technologies, USA) was performed. Results: Eight novel CNVs in 9 patients not described in healthy individuals and not associated with any disease were indentified implicating regions at 11q22.3, 5q33.1, 3p26.3, 15q11.1-q11.2, 15q22.2, 1q25.1-q25.2, 7q21.3, 2q12.3. They include candidate genes DDX10 (putative RNA helicase), IL17B (cytokine, primarily localized to neuronal cell bodies), CNTN6 (may play a role in the formation of axon connections), TLN2 (plays a role in cell adhesion and recycling of synaptic vesicles), TNR (an extracellular matrix protein, expressed primarily in the central nervous system), ASTN1 (a neuronal adhesion molecule), PON1 (detoxifies organophosphate neurotoxicants), and SLC5A7 (choline transporter in the brain and periphery). Conclusions: Previously unknown CNVs, containing genes responsible for proper central nervous system functioning, were detected in 13% of patients. The novel CNVs and genes identified by aCGH may help discovering new etiological mechanisms of MR. This study was supported by European Community's Seventh Framework Programme, CHERISH (project 223692) and by Federal Program (grant 8727). [ABSTRACT FROM AUTHOR]

Early stages of human embryonic development are characterized by the spatiotemporal coincidence of events of total epigenetic genome reprogramming and elevated level of mosaic forms of numerical chromosome abnormalities. It is possible that the abnormal reprogramming of various regions of the genome can lead to violations of local epigenetic chromatin organization and gene expression, which affect the correct chromosome segregation during mitosis. In this study, a comparative analysis of the methylation index of LINE-1 retrotransposon, which largely reflects the methylation profile of the genome, is performed in placental tissues of spontaneous abortions with complete and mosaic forms of aneuploidy and with a normal karyotype, as well as in the control group of induced abortions of the first trimester of pregnancy. It was shown that extraembryonic mesoderm and chorionic cytotrophoblast of spontaneous abortions with chromosomal mosaicism are characterized by the highest index of LINE-1 methylation among all studied groups. At the same time, the excessive hypomethylation of transposable genetic element was registered in spontaneous abortions with normal karyotype. We hypothesize that violations of parental genome demethylation during epigenetic reprogramming at preimplantation stages of development may be associated with an increased frequency of mitotic errors in chromosome segregation, which leads to the formation of a mosaic karyotype. [ABSTRACT FROM AUTHOR]

The presence of an extra chromosome in the embryo karyotype often dramatically affects the fate of pregnancy. Trisomy 16 is the most common aneuploidy in first-trimester miscarriages. The present study identified changes in DNA methylation in chorionic villi of miscarriages with trisomy 16. Ninety-seven differentially methylated sites in 91 genes were identified (false discovery rate (FDR) < 0.05 and Δβ > 0.15) using DNA methylation arrays. Most of the differentially methylated genes encoded secreted proteins, signaling peptides, and receptors with disulfide bonds. Subsequent analysis using targeted bisulfite massive parallel sequencing showed hypermethylation of the promoters of specific genes in miscarriages with trisomy 16 but not miscarriages with other aneuploidies. Some of the genes were responsible for the development of the placenta and embryo (GATA3-AS1, TRPV6, SCL13A4, and CALCB) and the formation of the mitotic spindle (ANKRD53). Hypermethylation of GATA3-AS1 was associated with reduced expression of GATA3 protein in chorionic villi of miscarriages with trisomy 16. Aberrant hypermethylation of genes may lead to a decrease in expression, impaired trophoblast differentiation and invasion, mitotic disorders, chromosomal mosaicism and karyotype self-correction via trisomy rescue mechanisms. [ABSTRACT FROM AUTHOR]

The article discusses a study regarding the reactions of benzaldehyde dimethylhydrazone with phosphorous acids. It says that the reactions of the obtained hydrazone, diethyl, and diphenyl phosphites were performed under different conditions, in which catalysts are used in the Pudovik reaction. It adds that the slow reaction of diphenyl phosphite with hydrazone I was accelerated by the introduction of trimethylchlorosilane.

Purpose: High frequency of aneuploidy in meiosis and cleavage stage coincides with waves of epigenetic genome reprogramming that may indicate a possible association between epigenetic mechanisms and aneuploidy occurrence. This study aimed to assess the methylation level of the long interspersed repeat element 1 (LINE-1) retrotransposon in chorionic villi of first trimester miscarriages with a normal karyotype and aneuploidy. Methods: The methylation level was assessed at 19 LINE-1 promoter CpG sites in chorionic villi of 141 miscarriages with trisomy of chromosomes 2, 6, 8–10, 13–15, 16, 18, 20–22, and monosomy X using massive parallel sequencing. Results: The LINE-1 methylation level was elevated statistically significant in chorionic villi of miscarriages with both trisomy (45.2 ± 4.3%) and monosomy X (46.9 ± 4.2%) compared with that in induced abortions (40.0 ± 2.4%) (p < 0.00001). The LINE-1 methylation levels were specific for miscarriages with different aneuploidies and significantly increased in miscarriages with trisomies 8, 14, and 18 and monosomy X (p < 0.05). The LINE-1 methylation level increased with gestational age both for group of miscarriages regardless of karyotype (R = 0.21, p = 0.012) and specifically for miscarriages with trisomy 16 (R = 0.48, p = 0.007). LINE-1 methylation decreased with maternal age in miscarriages with a normal karyotype (R = − 0.31, p = 0.029) and with trisomy 21 (R = − 0.64, p = 0.024) and increased with paternal age for miscarriages with trisomy 16 (R = 0.38, p = 0.048) and monosomy X (R = 0.73, p = 0.003). Conclusion: Our results indicate that the pathogenic effects of aneuploidy in human embryogenesis can be supplemented with significant epigenetic changes in the repetitive sequences. [ABSTRACT FROM AUTHOR]

The gene expression of mTOR, autophagy-related ULK1, caspase 3, CDK-inhibitor p21, and TNFα was measured in the peripheral blood of osteoarthritic (OA) patients at different stages of the disease aiming to establish a gene expression profile that might indicate the activity of the disease and joint destruction. Whole blood of 65 OA outpatients, 27 end-stage OA patients, 27 healthy volunteers, and knee articular cartilages of 28 end-stage OA patients and 26 healthy subjects were examined. OA outpatients were subjected to clinical testing, ultrasonography, and radiographic and WOMAC scoring. Protein levels of p70-S6K, p21, and caspase 3 were quantified by ELISA. Gene expression was measured using real-time RT-PCR. Upregulation of mTOR gene expression was observed in PBMCs of 42 OA outpatients ("gHigh mTOR expression subset") and in PBMCs and articular cartilages of all endstage OA patients. A positive correlation between mTOR gene expression in PBMCs and cartilage was observed in the end-stage OA patients. 23 OA outpatients in the "Low mTOR expression subset" exhibited significantly lower mTOR gene expression in PBMCs compared to healthy controls. These "Low mTOR" subset subjects experienced significantly more pain upon walking, and standing and increased total joint stiffness versus "High mTOR" subset, while the latter more often exhibited synovitis. The protein concentrations of p70-S6K, p21, and caspase 3 in PBMCs were significantly lower in the "Low" subset versus "High" subset and end-stage subjects. Increases in the expression of mTOR in PBMCs of OA patients are related to disease activity, being associated with synovitis more than with pain. [ABSTRACT FROM AUTHOR]

Abstract: Differential scanning calorimetry and IR-spectroscopy have been used to study the depolymerization of the 2D tetragonal (T) polymerized phase of C60 at p =1atm. The depolymerization enthalpy obtained was 17.7±1.7kJ per mole of C60. Experimental enthalpies of depolymerization along with the lattice energies calculated by the atom–atom potential method were combined into the thermochemical cycles to account for the trends in the relative stability of the polymerized phases of C60. Surprisingly low depolymerization enthalpy of 2D rhombohedral (R) phase compared to 1D orthorhombic (O) and 2D T-phases was explained by the unfavorable packing energy of the isolated rhombohedral layers into R-crystal lattice, though the averaged C60 =C60 bond energy was also lower for R- than for O- and T- phases, being 31, 42 and 43kJ/mol, respectively. Results of DFT quantum chemical calculations of the energetics of C60 polymers were in qualitative agreement with this trend. The mechanism of depolymerization appeared to be significantly different for R-phase compared to other polymers. While decomposition of O- and T-phases occurred in one step without any IR-detectable intermediate species, depolymerization of R-phase was found to be at least a two-step process. Comparison of experimental and DFT simulated IR-spectra suggested that intermediate species were cyclic trimers or similar oligomers. [Copyright &y& Elsevier]

Differential Scanning Calorimetry and infra-red spectroscopy have been used to study the depolymerization of the two pressure polymerized phases of C60, i.e., rhombohedral (R) and orthorhombic (O) into monomeric C60 at p=1 atm. The depolymerization enthalpies obtained were 10.3 ± 0.5 and 20.1 ± 0.6 kJ/mol for R-, O-phases, respectively. The R-phase, prepared at 1025–1050 K and 6 GPa (‘magnetic carbon’) demonstrated the depolymerization behaviour, similar to the typical R-phase. Part of the p–T-phase diagram of C60 was sketched in, using experimental and literature data. [Copyright &y& Elsevier]

By adiabatic vacuum calorimetry the temperature dependence of heat capacity for crystalline dimer of fullerene C60 has been determined in the range 6–340 K at standard pressure. Between 46 and 56 K, a glass-like transition of the dimer, the nature of which is, probably, similar to that described for C60, has been found. The results were used to calculate the thermodynamic functions of the dimer: the heat capacity Cp∘(T), enthalpy H°(T)−H°(0), entropy S°(T)−S°(0) and Gibbs function G°(T)−H°(0) over the range from T→0 to 340 K. For T<60 K the fractal dimension D in the heat capacity function of the multifractal variant of the Debye’s theory of heat capacity was estimated and in the 20–45 K range D was found to be 1. That indicates a chain structure of the dimer. The heat capacities of the dimer have been compared to those of the initial fullerite C60. The standard entropy of formation of the crystalline dimer from graphite, at T=298.15 K and at standard pressure, and the entropies of transition of the initial fullerite C60 to the crystalline dimer have been calculated. [Copyright &y& Elsevier]

Single crystals of the 2D polymerized tetragonal phase of C60 without orientational domains were obtained under high pressure and high temperature. The crystal structure of this phase was resolved using single crystal X-ray diffraction data. The cell parameters are a=9.064(3) and c=15.039(8) A˚ with the space group P42/mmc and Z=2. A structural model of this phase proposed early was confirmed and refined to final R=0.075. The structure is slightly disordered. It consists of a random combination of the P42/mmc layers (84%) and of the Immm layers (16%), along the c-axis. [Copyright &y& Elsevier]

Discusses the varied magnetic properties of the nanostructured forms of molecular carbon. Rise of superconducting and ferromagnetic properties in pure graphite; Features of typical ferromagnets; Indication of Curie temperature.