Introduction. Schizophrenia (SZ) increases the level of cell death, leading to an increase in the concentration of circulating cell-free DNA (cfDNA). Ribosomal DNA (rDNA) contains many unmethylated ...CpG motifs that stimulate TLR9-MyD88-NF-κB signaling and the synthesis of proinflammatory cytokines. The number of rDNA copies in the genomes of SZ patients is increased; therefore, we expect that the concentration of cell-free rDNA in the plasma of the SZ patients also increases. This may be one of the explanations of the proinflammatory cytokine increase that is often observed in SZ. The major research question is what is the rDNA copy number in cfDNA (cf-rDNA CN) and its putative role in schizophrenia? Materials and Methods. We determined cfDNA concentration (RNase A/proteinase K/solvent extraction; fluorescent dye PicoGreen) and endonuclease activity (NA) of blood plasma (radial diffusion method) in the untreated male SZ group (N=100) and in the male healthy control group (HC) (N=96). Blood leukocyte DNA and cfDNA rDNA CN were determined with nonradioactive quantitative hybridization techniques. Plasma concentration of cf-rDNA was calculated. Results. In the subjects from the SZ group, the mean cfDNA plasma concentration was twofold higher and NA of the plasma was fourfold higher than those in the healthy controls. rDNA CN in the blood leukocyte genome and in the cfDNA samples in the SZ group was significantly higher than that in the HC group. cf-rDNA concentration was threefold higher in the SZ group. Conclusion. Despite the abnormally high endonuclease activity in the blood plasma of SZ patients, the circulating cfDNA concentration is increased. Fragments of cf-rDNA accumulate in the blood plasma of SZ patients. Potentially, SZ patients’ cfDNA should be a strong stimulating factor for the TLR9-MyD88-NF-κB signaling pathway.
Cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss are among the most common autosomal recessive diseases, which require carrier screening. The ...evaluation of population allele frequencies (AF) of pathogenic variants in genes associated with these conditions and the choice of the best genotyping method are the necessary steps toward development and practical implementation of carrier-screening programs. We performed custom panel genotyping of 3821 unrelated participants from two Russian population representative samples and three patient groups using real-time polymerase chain reaction (PCR) and next generation sequencing (NGS). The custom panel included 115 known pathogenic variants in the CFTR, PAH, SERPINA1, and GJB2 genes. Overall, 38 variants were detected. The comparison of genotyping platforms revealed the following advantages of real-time PCR: relatively low cost, simple genotyping data analysis, and easier detection of large indels, while NGS showed better accuracy of variants identification and capability for detection of additional pathogenic variants in adjacent regions. A total of 23 variants had significant differences in estimated AF comparing with non-Finnish Europeans from gnomAD. This study provides new AF data for variants associated with the studied disorders and the comparison of genotyping methods for carrier screening.
The first results of paleogeographic study at estuary of the Katynka river allow to reconstruct the dynamics of vegetation in this part of the Dnieper floodplain for about 5 millennia and identify ...some traces of Neolithic, Early Iron Age and Medieval human activity. The most prominent anthropogenic transformation of landscapes (signs of slash-and-burn agriculture) was associated with the late Holocene «Gnezdovo» buried soil dated 2-5 centuries AD.
The studies of past climatic changes form the basis for predicting our future anthropogenic world and are among the most prominent topics in current Earth sciences. Although the Cretaceous is ...generally considered as a greenhouse period in Earth's history, a number of significant cooling events based on an array of climatic proxies have been identified. Here we present the first data on Berriasian (Ryazanian) glendonite findings from the paleontologically well dated Lower Cretaceous succession of northeastern Siberia. Based on well calibrated Buchia and ammonite biostratigraphy, the stratigraphic interval across which the glendonites occur is restricted to the late Berriasian. Stable carbon isotope (δ13C) values of the studied glendonites clearly suggest the precipitation of ikaite from marine water without any significant contamination from biogenic methane. Our results, when integrated with other available paleoclimatic proxies from elsewhere in the high latitudes, suggest a revision of the initiation of Early Cretaceous cooling in the high latitudes from the Valanginian to the late Berriasian. All known occurrences of Lower Cretaceous glendonites in both the northern and southern hemispheres are reviewed.
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•Oldest Cretaceous glendonites ever known are discovered.•This record suggesting the Berriasian onset of the Early Cretaceous cooling.•Stratigraphic distribution of glendonites provides evidence for multiple short-time cooling events.•All Lower Cretaceous glendonite occurrences are reviewed.
Spin‐crossover metal complexes represent important building blocks for a future generation of electronic and optical devices. Pentacoordinated o‐iminosemiquinonate iron(III) complexes are able to ...demonstrate spin transitions between high spin (HS) and intermediate spin (IS) states under the influence of temperature or irradiation. Studied (MeimSQ)2FeBr sample showed a broad magnetic transition in the temperature region from 30 K to 300 K. Remarkably that observed behavior of magnetization can be interpreted with two controversial models. In the first model, the values of the effective magnetic moment at low temperature and high temperature can be assigned to the IS and HS magnetic moment of ferric ion coupled antiferromagnetically to radical anion ligands. In the second model, the metal spin on metal center remains IS in the whole temperature interval, while the mutual orientation of three magnetic moments in the molecule undergo changes due to exchange interactions. In this work we apply density functional theory and X‐ray absorption spectroscopy to unravel the origin of magnetic properties of the complex. Temperature‐induced changes of interatomic distances in the first coordination sphere support the second model. Such comprehensive analysis of the magnetic properties makes it possible to shed light on the nature of spin transitions in complexes of transition metals with open‐shell ligands, which are often complicated by strong exchange interactions.
Unusual temperature‐dependent magnetization in the pentacoordinate ferric bis‐o‐iminosemiquinonate complex is not related to the spin crossover. X‐ray absorption spectroscopy quantified structural deformations originating from spin transition upon cooling. DFT simulations in broken symmetry approach explain these geometry changes by strong exchange interactions between spins on Fe and ligands.
The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia ...through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally.
Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases.
Of the 61 612 individuals in the registry, 42 167 adults (21 999 53·6% women) from 56 countries were included in the study. Of these, 31 798 (75·4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84·2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46·2 years (IQR 34·3–58·0); median age at diagnosis of familial hypercholesterolaemia was 44·4 years (32·5–56·5), with 40·2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17·4% (2·1% for stroke and 5·2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81·1%) were receiving statins and 3691 (21·2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5·43 mmol/L (IQR 4·32–6·72) among patients not taking lipid-lowering medications and 4·23 mmol/L (3·20–5·66) among those taking them. Among patients taking lipid-lowering medications, 2·7% had LDL cholesterol lower than 1·8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin–kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1·8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p<0·001).
Familial hypercholesterolaemia is diagnosed late. Guideline-recommended LDL cholesterol concentrations are infrequently achieved with single-drug therapy. Cardiovascular risk factors and presence of coronary disease were lower among non-index cases, who were diagnosed earlier. Earlier detection and greater use of combination therapies are required to reduce the global burden of familial hypercholesterolaemia.
Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron.
Peatlands play an important role in the global carbon cycle but have been exploited over many centuries, which reduces their carbon storage capacity. To investigate peatland development during the ...late Holocene and their restoration after peat extraction, we applied a multi-proxy paleoecological (pollen, plant macrofossils, testate amoebae, loss on ignition, peat humification, etc.) approach to undisturbed and floating vegetation mat deposits of the Gorenki peatland (Meshchera Lowlands, East European Plain). Peatland development started around 2550 before the common era (BCE) as a waterlogged eutrophic birch forest (terrestrial paludification) surrounded by a broadleaf forest. Around 2400 BCE, the peatland turned into an open mire with Sphagnum mosses, sedges, and willows. During 900–800 BCE, the mire transformed into a wet mesotrophic peatland surrounded by a spruce forest. The first human settlements and deforestation around 300–400 CE coincided with oligotrophization of the mire. The growth of the Slavic population in the region in 14th century CE caused transformation of indigenous spruce–broadleaf forests into croplands, and the mire became drier and forested. Since peat extraction was abandoned in the beginning of 20th century CE, the mire has undergone self-restoration starting with the formation of a Sphagnum cuspidatum/obtusum quagmire on the floating peat remains. The Sphagnum mat stabilized during 1960–2000 CE. During the last twenty years, agricultural activity decreased and pine forests were restored in the adjacent area; the floating mat became drier and more oligotrophic, which can lead to the formation of a bog in the absence of considerable anthropogenic impact.
Mechanical alloys Mg + 10 wt.% Ti and Mg + 5 wt.% Ti + 5 wt.% TiC (MAs) were synthesized by reactive mechanical alloying (RMA). Thermal stability and hydrogen desorption kinetics of the nanosized MgH
...2
phase in the obtained MAs were examined by means of thermal desorption spectroscopy at a hydrogen pressure of 0.1 MPa. The stabilizing effect of Ti on the nanocrystalline structure and growth of the crystallites (grains) of the MgH
2
phase during the cycling was also evaluated. It has been established that the complex doping by Ti and TiC leads to a significant improvement in the desorption of hydrogen in the nanosized MgH
2
phase of MAs. The role of Ti and TiC as alloying elements in improving the hydrogen desorption kinetics of MAs was studied. The catalytic effect of adding 5 wt.% Ti + 5 wt.% TiC to magnesium in improving the kinetics of hydrogen desorption is significantly lower than the catalytic effect of adding 10 wt.% Ti. Due to such alloying, the decrease in the thermodynamic stability of MgH
2
is not established. The average rate of the reaction does not depend on the hydrogen concentration and is equal to the rate constant k = = k
0
exp(–Ea/RT) (the Arrhenius equation). The tested materials showed high potential as hydrogen storage alloys, especially for stationary applications.
Introduction: Differential diagnostics of early-onset schizophrenia and autism spectrum disorders (ASD) are a problem of child psychiatry. The prognosis and relevant treatment are to a large degree ...determined by the correctness of diagnosis. We found earlier that leucocyte DNA of adult schizophrenia patients contained significantly larger copy numbers of ribosomal repeats (rDNA) coding for rRNA, than DNA of mentally healthy controls. Aim: To compare the contents of ribosomal repeats in the leucocyte DNA of children with schizophrenia, children with ASD, and healthy age-matched controls to estimate the possibility of using this genetic trait in the differential diagnostics of the two types of disorders. Patients and methods: Blood samples of patients with infantile autism (A—F84.0 according to ICD-10, N = 75) and with childhood-onset schizophrenia (SZ—F20.8 according to ICD-10, N = 43) were obtained from the Child Psychiatry Department of the Mental Health Research Center. The healthy control blood samples (HC, N = 86) were taken from the Research Centre for Medical Genetics collection. The recruitment of cases was based on the clinical psychopathologic approach. DNA was extracted from blood leukocytes with organic solvents. Nonradioactive quantitative hybridization technique was applied for determining the abundance of ribosomal repeats in the genomes. Statistical processing was performed using StatPlus, Statgraphics and MedCalc. Findings: DNA derived from SZ cases contained 565 ± 163 rDNA copies, which is significantly (p < 10−6) higher than the rDNA content in ASD cases (405 ± 109 copies) and controls (403 ± 86 copies). The HC and A groups did not differ by rDNA copy number (p > 0.4). The genetic trait “rDNA copy number in patient’s genome” can potentially be applied as an additional marker in differential diagnostics of childhood-onset schizophrenia and autism spectrum disorders.
A number of pentacoordinated gallium complexes iSQ2GaR (1–7) (R = Et (1), Me (2), N3 (3), Cl (4), Br (5), I (6), NCS (7)) where iSQ is a radical anion of ...4,6-di-tert-butyl-N-(2,6-diisopropylphenyl)-o-iminobenzoquinone were synthesized, and crystalline samples of 1–7 were characterized using magnetic susceptibility measurements. The character of magnetic exchange interaction between spins of o-iminosemiquinonate radicals was found to be strongly influenced by the nature of the apical substituent. The antiferromagnetic coupling is predominant when the apical position is occupied by halogens or other tested inorganic anions, and the value of exchange interaction parameter varies from −99 to −176 K for R = I and NCS, respectively. In the case of alkyl groups the ferromagnetic exchange prevails and, as the result, the triplet ground state for pentacoordianted biradical compounds was observed. Compounds 1–7 demonstrate a biradical X-band EPR spectrum in frozen toluene matrix. The molecular structures of 4, 6, and 7 have been established by single-crystal X-ray analysis. A computational DFT UB3LYP/6-31G(d,p) study was performed on complexes 1–7 in order to understand the reason for changes in the magnetic behavior of the related diradical gallium compounds. The calculations showed that the magnetic behavior of the complexes with inorganic anions is conditioned by the presence of antiferromagnetic exchange channel formed as a consequence of overlapping between donor atomic orbitals of iminoquinone with π-orbitals of halogen atoms (4–6) or nitrogen atom (3, 7).
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