miR-122 is a highly expressed liver microRNA that is activated perinatally and aids in regulating cholesterol metabolism and promoting terminal differentiation of hepatocytes. Disrupting expression ...of miR-122 can re-activate embryo-expressed adult-silenced genes, ultimately leading to the development of hepatocellular carcinoma (HCC). Here we interrogate the liver transcriptome at various time points after genomic excision of miR-122 to determine the cellular consequences leading to oncogenesis. Loss of miR-122 leads to specific and progressive increases in expression of imprinted clusters of microRNAs and mRNA transcripts at the Igf2 and Dlk1-Dio3 loci that could be curbed by re-introduction of exogenous miR-122. mRNA targets of other abundant hepatic microRNAs are functionally repressed leading to widespread hepatic transcriptional de-regulation. Together, this reveals a transcriptomic framework for the hepatic response to loss of miR-122 and the outcome on other microRNAs and their cognate gene targets.
We present a combination of independent techniques in order to characterize vulcanized natural rubber elastomer networks. We combine solid state proton multiple-quantum NMR, equilibrium swelling, ...mechanical experiments, and in-situ tensile X-ray scattering measurements, all of them giving access to the segmental orientation effects in relation to the cross-linking of the systems. By means of the combination of these techniques, we investigate a set of unfilled natural rubber networks with different levels of cross-linking. The relevance of this work is the application of this approach in order to study the reinforcement effect in filled elastomers with nanoparticles in a following work.
This paper reports simple strategies to fabricate self-assembled artificial tubular and filamentous systems from a low molecular weight gelator (LMWG). In the first strategy, tubular 'core-shell' gel ...structures based on the dibenzylidenesorbitol-based LMWG DBS-CONHNH
were made in combination with the polymer gelator (PG) calcium alginate. In the second approach, gel filaments based on DBS-CONHNH
alone were prepared by wet spinning at elevated concentrations using a 'solvent-switch' approach. The higher concentrations used in wet-spinning prevent the need for a supporting PG. Furthermore, this can be extended into a 3D-printing method, with the printed LMWG objects showing excellent stability for at least a week in water. The LMWG retains its unique ability for
precious metal reduction, yielding Au nanoparticles (AuNPs) within the tubes and filaments when they are exposed to AuCl
solutions. Since the gel filaments have a higher loading of DBS-CONHNH
, they can be loaded with significantly more AuNPs. Cytotoxicity and viability studies on human mesenchymal stem cells show that the DBS-CONHNH
and DBS-CONHNH
/alginate hybrid gels loaded with AuNPs are biocompatible, with the presence of AuNPs enhancing stem cell metabolism. Taken together, these results indicate that DBS-CONHNH
can be shaped and 3D-printed, and has considerable potential for use in tissue engineering applications.
tRNA-derived small RNAs (tsRNAs) have been implicated in many cellular processes, yet the detailed mechanisms are not well defined. We previously found that the 3′ end of Leu-CAG tRNA-derived small ...RNA (LeuCAG3′tsRNA) regulates ribosome biogenesis in humans by maintaining ribosomal protein S28 (RPS28) levels. The tsRNA binds to coding (CDS) and non-coding 3′ UTR sequence in the RPS28 mRNA, altering its secondary structure and enhancing its translation. Here we report that the functional 3′ UTR target site is present in primates while the CDS target site is present in many vertebrates. We establish that this tsRNA also regulates mouse Rps28 translation by interacting with the CDS target site. We further establish that the change in mRNA translation occurred at a post-initiation step in both species. Overall, our results suggest that LeuCAG3′tsRNA might maintain ribosome biogenesis through a conserved gene regulatory mechanism in vertebrates.
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•LeuCAG3′tsRNA target site in the RPS28 coding sequence is conserved in vertebrates•LeuCAG3′tsRNA regulates RPS28 translation after the initiation step in humans and mice•LeuCAG3′tsRNA-regulated translation is conserved between humans and mice•tsRNA-regulated translational mechanism might be conserved among vertebrates
Kim et al. determined that the LeuCAG3′tsRNA target site in the RPS28 coding sequence (CDS) is conserved in vertebrates and established that the tsRNA regulation of RPS28 mRNA translation is conserved between humans and mice. Their results suggest that the tsRNA-regulated mRNA translation might be a conserved process.
Ethnographic semantics is the description of semantic characteristics that are culturally revealing. In anthropology it has come to include a number of different types of analysis which have so far ...been used mostly in studies of kinship and folk science. These are contrast-level mapping, componential analysis, programmed specification, and various uses of semantic rules, notably reduction analysis. Contrast-level study is the mapping of native words in hierarchies of different levels of generality. Componential analysis is the breakdown of terms into the distinctive features that are necessary and sufficient to distinguish them from each other. Programmed specification is a carefully controlled use of native phrases and statements to elicit further native statements about a given topic in a way that preserves as much of the native thought pattern as possible. The use of semantic rules permits one to "generate" statements that are acceptable to native speakers or allows the reduction of a series of terms or phrases to a focal type or to semantic primitives in ways that are theoretically productive of further semantic and ethnologic insight. In working with semantics, the anthropologists should not preoccupy himself problems of homonyny, which are sterile in the absence of informant validation and written records of the language. Culturally based validation through experimental semantics, with careful attention to the various ways in which thought and meaning interrelate and how they "come throught" in translation, will reduce arbitrariness. The treatment of semantic problems by philosophers (e.g., Quine's principle of the indeterminacy of translation and the Quine-Carnap controversy over intensional meaning) can be illuminating to the anthropologist in this respect. With the beginning of the 1960's, I feel that social anthropology has entered a new phase of development. Higher standards of excellence are being brought to bear in ethnographic descriptions, and semantics has come to occupy a larger place in them. The greatest emphasis now seems to be on ethnographic semantics-the semantic description of the communicative codes of a particular speech community. As more investigators become interested in general ethnology, however, there should be an increasing interest in ethnologic semantics, which deals with the theoretical vocabulary and symbolic manipulations of ethnology, and area which remains undeveloped.
We examine whether inclusion of artificial intelligence (AI)-enabled retinal vasculometry (RV) improves existing risk algorithms for incident stroke, myocardial infarction (MI) and circulatory ...mortality.
AI-enabled retinal vessel image analysis processed images from 88 052 UK Biobank (UKB) participants (aged 40-69 years at image capture) and 7411 European Prospective Investigation into Cancer (EPIC)-Norfolk participants (aged 48-92). Retinal arteriolar and venular width, tortuosity and area were extracted. Prediction models were developed in UKB using multivariable Cox proportional hazards regression for circulatory mortality, incident stroke and MI, and externally validated in EPIC-Norfolk. Model performance was assessed using optimism adjusted calibration, C-statistics and R
statistics. Performance of Framingham risk scores (FRS) for incident stroke and incident MI, with addition of RV to FRS, were compared with a simpler model based on RV, age, smoking status and medical history (antihypertensive/cholesterol lowering medication, diabetes, prevalent stroke/MI).
UKB prognostic models were developed on 65 144 participants (mean age 56.8; median follow-up 7.7 years) and validated in 5862 EPIC-Norfolk participants (67.6, 9.1 years, respectively). Prediction models for circulatory mortality in men and women had optimism adjusted C-statistics and R
statistics between 0.75-0.77 and 0.33-0.44, respectively. For incident stroke and MI, addition of RV to FRS did not improve model performance in either cohort. However, the simpler RV model performed equally or better than FRS.
RV offers an alternative predictive biomarker to traditional risk-scores for vascular health, without the need for blood sampling or blood pressure measurement. Further work is needed to examine RV in population screening to triage individuals at high-risk.
Facile stoichiometric and phase selective synthesis of doped/alloyed metal chalcogenide colloidal quantum dots has been an important pursuit because of the opportunity for tunable photoconductivity. ...Herein, the structural and optical properties of relatively monodispersed copper indium sulphide incorporated with Ag+ ions, i.e., AgxCuyInS2 (Ag:CIS) quantum dots (average diameter of 4.9 ± 0.6 nm) synthesized via a hot-injection colloidal method are investigated. The Ag:CIS quantum dots exhibit a degree of wurtzite to chalcopyrite phase change with increasing Ag+ concentration (1.1–6.8%) under primarily kinetic synthetic conditions at 180 °C for 10 minutes using copper(ii) hexafluoroacetylacetonate hydrate, indium(iii) and silver(i) diethyldithiocarbamate precursors. The indium-rich and copper-deficient quantum dots are close to the CuInS2 stoichiometry with tunable bandgaps between 1.60 and 1.81 eV influenced by Ag+ concentration, intrinsic defects, minimal quantum confinement and structural permutations. They exhibit broad photoluminescence emission via a dual radiative pathway with long decay lifetimes, τ1 (0.68–2.11 ± 0.02 μs) and τ2 (3.37–7.38 ± 0.20 μs), implicating donor–acceptor pair transitions of indium interstitials, Formula Omitted and/or indium–copper antisites, Formula Omitted to copper vacancies, Formula Omitted for low Ag+ concentrations but primarily silver interstitials, Formula Omitted to Formula Omitted for higher Ag+ concentrations. Importantly, this study is the first involving Ag+ ion-dependent wurtzite to chalcopyrite phase transformation of CIS quantum dots and with their long radiative emission lifetimes are potentially effective photo-absorbers in quantum dot solar cells.
Uterine endometrioid adenocarcinomas are known for their morphologic plasticity. In addition to a multiplicity of metaplasias, uterine endometrioid adenocarcinomas may also undergo high-grade ...divergent differentiation in the form of high-grade neuroendocrine carcinoma, neuroectodermal differentiation or carcinosarcoma; others may dedifferentiate completely. Here we describe 5 cases of uterine endometrioid adenocarcinomas with high-grade divergent differentiation showing a striking morphologic and immunophenotypic resemblance to cutaneous pilomatrix carcinoma. Specifically, the high-grade component in all cases exhibited solid, basaloid morphology with conspicuous tumor cell necrosis and the presence of shadow cells, accompanied by diffusely aberrant (nuclear and cytoplasmic) β-catenin expression as well as variably diffuse CDX2 expression. In addition, the high-grade component in all cases showed loss of ER and PAX8 expression, retained MMR expression, wild-type p53 expression, patchy p16 expression, and diffusely positive cytokeratin expression (AE1/AE3 and CK7); at least focal neuroendocrine marker expression was present in all cases. CK20 was negative in all cases, with the exception of very focal staining in a single case (2% of tumor cells). All 5 of our tumors had at least a focal conventional FIGO grade 1 component. In all 4 cases tested, the low-grade component retained both PAX8 and ER expression and had, at best, focally aberrant β-catenin expression. Two of our cases had molecular analysis performed and both harbored mutations in exon 3 of CTNNB1 as expected; molecular analysis also revealed that both cases lacked POLE or TP53 mutations and showed no microsatellite instability. The tumors in this series were uniformly aggressive. Four of the 5 patients in our cohort had available follow-up information; of these, 3/4 died of their disease within 14 mo of diagnosis and the fourth patient had distant metastatic disease at presentation and is alive with disease 1 mo following diagnosis. The 1 patient without follow-up information also had distant metastatic disease at presentation and was lost to follow-up 17 mo later. The cases described in this series (1) represent a highly aggressive CTNNB1-mutated subset of the "no specific molecular profile" category of endometrioid adenocarcinomas; (2) illustrate a form of high-grade divergent differentiation resembling cutaneous pilomatrix carcinoma already described in carcinomas at other anatomic sites; and (3) underscore the difficulty in recognizing this phenotype at distant metastatic sites, which are frequent even at the time of presentation, given the consistent loss of ER and PAX8 expression and concurrent CDX2 expression.
Deoxynivalenol (DON) requires no activation for toxicity, though susceptibility may reflect individual variations in detoxification. This study reports the measurement of un-metabolised urinary DON ...(free DON) and DOM-1 in samples previously analysed for the combined measure of free DON+DON-glucuronide (fD+DG), with a concentration >5ng/ml, for 34 UK adults. Four consecutive daily urine samples were analysed from twenty-two individuals, whilst from 12 individuals only a single sample was analysed. The mean (median) concentration of urinary fD+DG in this sub-set was 17.8ng/ml (13.8ng/ml), range 5.0–78.2ng/ml. In 23/34 (68%) individuals, free DON was detected, mean 2.4ng/ml; range 0.5–9.3ng/ml. Urinary DOM-1 was detected in 1/34 (3%) of individuals; present at ∼1% of urinary fD+DG concentration for that individual. The concentration of fD+DG combined was significantly correlated with urinary free DON (p<0.001, R2=0.65), but not with the percentage of free DON to fD+DG (p=0.615, R2=0.01), suggesting that the level of DON exposure did not affect the metabolism to DG within the range observed. In this survey most individuals had no detectable urinary DOM-1 and 68% did not detoxify all of the ingested DON to DON-glucuronide. This study needs to be extended to understand whether the fD / DG ratio provides a phenotypic measure of DON susceptibility.
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