Search Results (12)

This paper provides a critical analysis of the molecular mechanisms presently used to explain transcriptional strand asymmetries of single base substitution (SBS) signatures observed in cancer genomes curated at the Catalogue of Somatic Mutations in Cancer (COSMIC) database (Wellcome Trust Sanger Institute). The analysis is based on a deaminase-driven reverse transcriptase (DRT) mutagenesis model of cancer oncogenesis involving both the cytosine (AID/APOBEC) and adenosine (ADAR) mutagenic deaminases. In this analysis we apply what is known, or can reasonably be inferred, of the immunoglobulin somatic hypermutation (Ig SHM) mechanism to the analysis of the transcriptional stand asymmetries of the COSMIC SBS signatures that are observed in cancer genomes. The underlying assumption is that somatic mutations arising in cancer genomes are driven by dysregulated off-target Ig SHM-like mutagenic processes at non-Ig loci. It is reasoned that most SBS signatures whether of “unknown etiology” or assigned-molecular causation, can be readily understood in terms of the DRT-paradigm. These include the major age-related “clock-like” SBS5 signature observed in all cancer genomes sequenced and many other common subset signatures including SBS1, SBS3, SBS2/13, SBS6, SBS12, SBS16, SBS17a/17b, SBS19, SBS21, as well as signatures clearly arising from exogenous causation. We conclude that the DRT-model provides a plausible molecular framework that augments our current understanding of immunogenetic mechanisms driving oncogenesis. It accommodates both what is known about AID/APOBEC and ADAR somatic mutation strand asymmetries and provides a fully integrated understanding into the molecular origins of common COSMIC SBS signatures. The DRT-paradigm thus provides scientists and clinicians with additional molecular insights into the causal links between deaminase-associated genomic signatures and oncogenic processes. Full article

Four quaternary Zintl phase thermoelectric (TE) materials belonging to the Ba_1-xEu_xZn₂Sb₂ (x = 0.02(1), 0.04(1), 0.08(1), 0.15(1)) system were successfully synthesized using the molten Pb-flux or the conventional high-temperature reaction methods. Their crystal structures were characterized by both powder and single-crystal X-ray diffraction analyses, and all four isotypic title compounds adopted the orthorhombic BaCu₂S₂-type (Pnma, Z = 4, Pearson code oP20) structure. The radius ratio criterion, based on the cationic and anionic elements (i.e., r₊/r₋), was successfully verified in the title system, as in our previous reports, where r₊/r₋ > 1 for the BaCu₂S₂-type structure. A series of density functional theory calculations were performed using a hypothetical model with the idealized compositions of Ba_0.75Eu_0.25Zn₂Sb₂, and the results were compared with the ternary parental compound BaZn₂Sb₂ to understand the influence of Eu substituents in the Ba_1-xEu_xZn₂Sb₂ system. A similar overall shape of the density of states (DOS) curves and the near-constant DOS values at E_F before and after the cationic substitution suggest only marginal changes in the carrier concentration. Therefore, carrier mobility has a dominant role in rationalizing the observed variations in the electrical transport properties of the title system. Temperature-dependent TE property measurements proved that an increase in the Seebeck coefficient S and a decrease in electrical conductivity σ were observed as the Eu substituents gradually increased in the Ba_1-xEu_xZn₂Sb₂ system, although the overall S and σ values were lower than those in the parental compound BaZn₂Sb₂. The thermal conductivities of these title compounds were successfully lowered by phonon scattering, but due to the overall smaller electrical transport properties, the observed maximum ZT was 0.49 at 773 K for Ba_0.98(1)Eu_0.02Zn₂Sb₂. Full article

As a physical mutagen, carbon ion beam (CIB) irradiation can induce high-frequency mutation, which is user-friendly and environment-friendly in plant breeding. In this study, we resequenced eight mutant lines which were screened out from the progeny of the CIB-irradiated dehulled rice seeds. Among these mutants, CIB induced 135,535 variations, which include single base substitutions (SBSs), and small insertion and deletion (InDels). SBSs are the most abundant mutation, and account for 88% of all variations. Single base conversion is the main type of SBS, and the average ratio of transition and transversion is 1.29, and more than half of the InDels are short-segmented mutation (1–2 bp). A total of 69.2% of the SBSs and InDels induced by CIBs occurred in intergenic regions on the genome. Surprisingly, the average mutation frequency in our study is 9.8 × 10⁻⁵/bp and much higher than that of the previous studies, which may result from the relatively high irradiation dosage and the dehulling of seeds for irradiation. By analyzing the mutation of every 1 Mb in the genome of each mutant strain, we found some unusual high-frequency (HF) mutation regions, where SBSs and InDels colocalized. This study revealed the mutation mechanism of dehulled rice seeds by CIB irradiation on the genome level, which will enrich our understanding of the mutation mechanism of CIB radiation and improve mutagenesis efficiency. Full article

Early-onset breast cancer (EoBC), defined by a diagnosis <40 years of age, is associated with poor prognosis. This study investigated the mutational landscape of non-metastatic EoBC and the prognostic relevance of mutational signatures using 100 tumour samples from Alberta, Canada. The MutationalPatterns package in R/Bioconductor was used to extract de novo single-base substitution (SBS) and insertion–deletion (indel) mutational signatures and to fit COSMIC SBS and indel signatures. We assessed associations between these signatures and clinical characteristics of disease, in addition to recurrence-free (RFS) and overall survival (OS). Five SBS and two indel signatures were extracted. The SBS13-like signature had higher relative contributions in the HER2-enriched subtype. Patients with higher than median contribution tended to have better RFS after adjustment for other prognostic factors (HR = 0.29; 95% CI: 0.08–1.06). An unsupervised clustering algorithm based on absolute contribution revealed three clusters of fitted COSMIC SBS signatures, but cluster membership was not associated with clinical variables or survival outcomes. The results of this exploratory study reveal various SBS and indel signatures may be associated with clinical features of disease and prognosis. Future studies with larger samples are required to better understand the mechanistic underpinnings of disease progression and treatment response in EoBC. Full article

Standard surgery followed by radioactive iodine (¹³¹I, RAI) therapy are not curative for 5–20% of papillary thyroid carcinoma (PTC) patients with RAI refractory disease. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. Whole-exome sequencing was performed (at median depth 198x) on 66 RAI-refractory and 92 RAI-avid PTCs with patient-matched germline. RAI-refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins (p = 0.016) and the presence of lymph node metastases at primary diagnosis (p = 0.012); higher nonsilent tumor mutation burden (p = 0.011); TERT promoter (TERTp) mutation (p < 0.0001); and the enrichment of the APOBEC-related single-base substitution (SBS) COSMIC mutational signatures 2 (p = 0.030) and 13 (p < 0.001). Notably, SBS13 (odds ratio [OR] 30.4, 95% confidence intervals [CI] 1.43–647.22) and TERTp mutation (OR 41.3, 95% CI 4.35–391.60) were revealed to be independent predictors of RAI refractoriness in PTC (p = 0.029 and 0.001, respectively). Although SBS13 and TERTp mutations alone highly predicted RAI refractoriness, when combined, they significantly increased the likelihood of predicting RAI refractoriness in PTC. This study highlights the APOBEC SBS13 mutational signature as a novel independent predictor of RAI refractoriness in a distinct subgroup of PTC. Full article

Despite considerable advances in biomaterials-based bone tissue engineering technologies, autografts remain the gold standard for rehabilitating critical-sized bone defects in the oral and maxillofacial (OMF) region. A majority of advanced synthetic bone substitutes (SBS’s) have not transcended the pre-clinical stage due to inferior clinical performance and translational barriers, which include low scalability, high cost, regulatory restrictions, limited advanced facilities and human resources. The aim of this study is to develop clinically viable alternatives to address the challenges of bone tissue regeneration in the OMF region by developing ‘dual network composites’ (DNC’s) of calcium metaphosphate (CMP)—poly(vinyl alcohol) (PVA)/alginate with osteogenic ions: calcium, zinc and strontium. To fabricate DNC’s, single network composites of PVA/CMP with 10% (w/v) gelatine particles as porogen were developed using two freeze–thawing cycles and subsequently interpenetrated by guluronate-dominant sodium alginate and chelated with calcium, zinc or strontium ions. Physicochemical, compressive, water uptake, thermal, morphological and in vitro biological properties of DNC’s were characterised. The results demonstrated elastic 3D porous scaffolds resembling a ‘spongy bone’ with fluid absorbing capacity, easily sculptable to fit anatomically complex bone defects, biocompatible and osteoconductive in vitro, thus yielding potentially clinically viable for SBS alternatives in OMF surgery. Full article

This contribution deals with the mechanochemical synthesis, characterization, and thermoelectric properties of tetrahedrite-based materials, Cu_12-xM_xSb₄S₁₃ (M = Fe²⁺, Zn²⁺, Cd²⁺; x = 0, 1.5, 2). High-energy mechanical milling allows obtaining pristine and substituted tetrahedrites, after short milling under ambient conditions, of stoichiometric mixtures of the corresponding commercially available binary sulfides, i.e., Cu₂S, CuS, Sb₂S₃, and MS (M = Fe²⁺, Zn²⁺, Cd²⁺). All the target materials but those containing Cd were obtained as single-phase products; some admixture of a hydrated cadmium sulfate was also identified by XRD as a by-product when synthesizing Cu₁₀Cd₂Sb₄S₁₃. The as-obtained products were thermally stable when firing in argon up to a temperature of 350–400 °C. Overall, the substitution of Cu(II) by Fe(II), Zn(II), or Cd(II) reduces tetrahedrites’ thermal and electrical conductivities but increases the Seebeck coefficient. Unfortunately, the values of the thermoelectric figure of merit obtained in this study are in general lower than those found in the literature for similar samples obtained by other powder processing methods; slight compositional changes, undetected secondary phases, and/or deficient sintering might account for some of these discrepancies. Full article

A new series of triphenylantimony(V) 3-alkylthio/arylthio-substituted 4,6-di-tert-butylcatecholates of the type (3-RS-4,6-DBCat)SbPh₃, where R = n-butyl (1), n-hexyl (2), n-octyl (3), cyclopentyl (4), cyclohexyl (5), benzyl (6), phenyl (7), and naphthyl-2 (8), were synthesized from the corresponding catechol thioethers and Ph₃SbBr₂ in the presence of a base. The crystal structures of 1, 2, 3, and 5 were determined by single-crystal X-ray analysis. The coordination polyhedron of 1–3 is better described as a tetragonal pyramid with a different degree of distortion, while that for 5- was a distorted trigonal bipyramid (τ = 0.014, 0.177, 0.26, 0.56, respectively). Complexes demonstrated different crystal packing of molecules. The electrochemical oxidation of the complexes involved the catecholate group as well as the thioether linker. The introduction of a thioether fragment into the aromatic ring of catechol ligand led to a shift in the potential of the “catechol/o-semiquinone” redox transition to the anodic region, which indicated the electron-withdrawing nature of the RS group. The radical scavenging activity of the complexes was determined in the reaction with DPPH radical. Full article

High-energy ion beams are known to be an effective and unique type of physical mutagen in plants. However, no study on the mutagenic effect of argon (Ar) ion beam radiation on rice has been reported. Genome-wide studies on induced mutations are important to comprehend their characteristics for establishing knowledge-based protocols for mutation induction and breeding, which are still very limited in rice. The present study aimed to investigate the mutagenic effect of three ion beams, i.e., Ar, carbon (C) and neon (Ne) on rice and identify and characterize heritable induced mutations by the whole genome sequencing of six M₄ plants. Dose-dependent damage effects were observed on M₁ plants, which were developed from ion beam irradiated dry seeds of two indica (LH15, T23) and two japonica (DS551, DS48) rice lines. High frequencies of chlorophyll-deficient seedlings and male-sterile plants were observed in all M₂ populations (up to ~30% on M₁ plant basis); plants from the seeds of different panicles of a common M₁ plant appeared to have different mutations; the whole genome-sequencing demonstrated that there were 236–453 mutations in each of the six M₄ plants, including single base substitutions (SBSs) and small insertion/deletions (InDels), with the number of SBSs ~ 4–8 times greater than that of InDels; SBS and InDel mutations were distributed across different genomic regions of all 12 chromosomes, however, only a small number of mutations (0–6) were present in exonic regions that might have an impact on gene function. In summary, the present study demonstrates that Ar, C and Ne ion beam radiation are all effective for mutation induction in rice and has revealed at the genome level the characteristics of the mutations induced by the three ion beams. The findings are of importance to the efficient use of ion beam radiation for the generation and utilization of mutants in rice. Full article

Crystal-structure refinements in space group P2₁/c were performed on five grains of rathite with different types and degrees of thallium, silver, and antimony substitutions, as well as quantitative electron-microprobe analyses of more than 800 different rathite samples. The results of these studies both enlarged and clarified the complex spectrum of cation substitutions and the crystal chemistry of rathite. The [Tl⁺ + As³⁺] ↔ 2Pb²⁺ scheme of substitution acts at the structural sites Pb1, Pb2, and Me6, the [Ag⁺ + As³⁺] ↔ 2Pb²⁺ substitution at Me5, and the Sb-for-As substitution at the Me3 site only. The homogeneity range of rathite was determined to be unusually large, ranging from very Tl-poor compositions (0.16 wt%; refined single-crystal unit-cell parameters: a = 8.471(2), b = 7.926(2), c = 25.186(5) Å, β = 100.58(3)°, V = 1662.4(6) ų) to very Tl-rich compositions (11.78 wt%; a = 8.521(2), b = 8.005(2), c = 25.031(5) Å, β = 100.56(3)°, V = 1678.4(6) ų). The Ag content is only slightly variable (3.1 wt%–4.1 wt%) with a mean value of 3.6 wt%. The Sb content is strongly variable (0.20 wt%–7.71 wt%) and not correlated with the Tl content. With increasing Tl content (0.16 wt%–11.78 wt%), a clear increase of the unit-cell parameters a, b, and V, and a slight decrease of c is observed, although this is somewhat masked by the randomly variable Sb content. The revised general formula of rathite may be written as Ag_xTl_yPb_16−2(x+y)As_16+x+y−zSb_zS₄₀ (with 1.6 < x < 2, 0 < y < 3, 0 < z < 3.5). Based on Pb–S bond lengths, polyhedral characteristics and Pb-site bond-valence sums, we conclude that the Pb1 site is more affected by Tl substitution than the Pb2 site. When Tl substitution reaches values above 13 wt% (or 3 apfu), a new phase (“SR”), belonging to the rahite group, appears as lamellar exsolution intergrowths with Tl-rich rathite (11.78 wt%). Rathite is found only in the Lengenbach and Reckibach deposits, Binntal, Canton Wallis, Switzerland. Full article

Cation substitutional doping is an effective approach to modifying the electronic and thermal transports in Bi₂Te₃-based thermoelectric alloys. Here we present a comprehensive analysis of the electrical and thermal conductivities of polycrystalline Pb-doped p-type bulk Bi_0.48Sb_1.52Te₃. Pb doping significantly increased the electrical conductivity up to ~2700 S/cm at x = 0.02 in Bi_0.48-xPb_xSb_1.52Te₃ due to the increase in hole carrier concentration. Even though the total thermal conductivity increased as Pb was added, due to the increased hole carrier concentration, the thermal conductivity was reduced by 14–22% if the contribution of the increased hole carrier concentration was excluded. To further understand the origin of reduction in the thermal conductivity, we first estimated the contribution of bipolar conduction to thermal conductivity from a two-parabolic band model, which is an extension of the single parabolic band model. Thereafter, the contribution of additional point defect scattering caused by Pb substitution (Pb in the cation site) was analyzed using the Debye–Callaway model. We found that Pb doping significantly suppressed both the bipolar thermal conduction and lattice thermal conductivity simultaneously, while the bipolar contribution to the total thermal conductivity reduction increased at high temperatures. At Pb doping of x = 0.02, the bipolar thermal conductivity decreased by ~30% from 0.47 W/mK to 0.33 W/mK at 480 K, which accounts for 70% of the total reduction. Full article

In this paper, a rapid and simple method to determine the optimal temperature conditions for denaturant electrophoresis using a temperature-controlled on-chip capillary electrophoresis (CE) device is presented. Since on-chip CE operations including sample loading, injection and separation are carried out just by switching the electric field, we can repeat consecutive run-to-run CE operations on a single on-chip CE device by programming the voltage sequences. By utilizing the high-speed separation and the repeatability of the on-chip CE, a series of electrophoretic operations with different running temperatures can be implemented. Using separations of reaction products of single-stranded DNA (ssDNA) with a peptide nucleic acid (PNA) oligomer, the effectiveness of the presented method to determine the optimal temperature conditions required to discriminate a single-base substitution (SBS) between two different ssDNAs is demonstrated. It is shown that a single run for one temperature condition can be executed within 4 min, and the optimal temperature to discriminate the SBS could be successfully found using the present method. Full article