Pancreatic Ductal adenocarcinoma (PDAC) is an aggressive cancer commonly exhibiting KRAS-activating mutations. Alcohol contributes to the risk of developing PDAC in humans, and murine models have ...shown alcohol consumption in the context of KRAS mutation in the pancreas promotes the development of PDAC. The molecular signatures in pancreas cells altered by alcohol exposure in the context of mutant KRAS could identify pathways related to the etiology of PDAC. In this study, we evaluated the combined effects of alcohol exposure and KRAS mutation status on the transcriptome and proteome of pancreatic HPNE cell models. These analyses identified alterations in transcription and translational processes in mutant KRAS cells exposed to alcohol. In addition, multi-omics analysis suggests an increase in the correlation between mRNA transcript and protein abundance in cells exposed to alcohol with an underlying KRAS mutation. Through differential co-expression, SERPINE1 was found to be influential for PDAC development in the context of mutant KRAS and ethanol. In terms of PDAC subtypes, alcohol conditioning of HPNE cells expressing mutant KRAS decreases the Inflammatory subtype signature and increases the Proliferative and Metabolic signatures, as we previously observed in patient samples. The alterations in molecular subtypes were associated with an increased sensitivity to chemotherapeutic agents gemcitabine, irinotecan, and oxaliplatin. These results provide a framework for distinguishing the molecular dysregulation associated with combined alcohol and mutant KRAS in a pancreatic cell line model.
One of the most effective ways to advance the performance of quantum computers and quantum sensors is to increase the number of qubits or quantum resources in the system. A major technical challenge ...that must be solved to realize this goal for trapped-ion systems is scaling the delivery of optical signals to many individual ions. In this paper we demonstrate an approach employing waveguides and multi-mode interferometer splitters to optically address multiple
Yb
ions in a surface trap by delivering all wavelengths required for full qubit control. Measurements of hyperfine spectra and Rabi flopping were performed on the E2 clock transition, using integrated waveguides for delivering the light needed for Doppler cooling, state preparation, coherent operations, and detection. We describe the use of splitters to address multiple ions using a single optical input per wavelength and use them to demonstrate simultaneous Rabi flopping on two different transitions occurring at distinct trap sites. This work represents an important step towards the realization of scalable integrated photonics for atomic clocks and trapped-ion quantum information systems.
Increasing intake of folic acid would be a relatively cheap and simple way of reducing heart disease, if it works. Can we draw a definitive conclusion from the current evidence?
Background
Idiopathic junctional ectopic tachycardia (JET) may still be difficult to control with antiarrhythmic therapy. Transcatheter ablation can be challenging and may be associated with a high ...risk of unintended atrioventricular block. The objective of this manuscript is to report the procedural technique, the location of the successful ablation, and the procedural characteristics while utilizing 3D mapping for cryoablation of JET.
Methods
A retrospective analysis was performed on all patients who had undergone cryothermal ablation for the treatment of JET at a single center. Patient, arrhythmia, and procedural information and long‐term outcomes were evaluated.
Results
Thirteen patients with JET were treated by cryothermal ablation. The JET arrhythmia burden varied greatly, generally with inadequate control on medications. Left ventricular dilation was present in three patients, and one patient had dilated cardiomyopathy. The median age at the time of procedure was 13 years, with median weight of 54.1 kg. The ectopic focus was ablated in 11/13 patients within the lower 2/3 of the triangle of Koch (TOK) with cryotherapy. Ablations, which were not successful, low in the TOK were associated with substantially longer procedures, and had a higher risk of recurrence. There was late resolution of the arrhythmia in two of three acutely unsuccessful ablations. There were no complications.
Conclusion
In the majority of patients JET can be safely ablated with the use of cryotherapy. Foci not identified in the lower 2/3 of the TOK are associated with longer procedures, more lesions, and decreased chance for long‐term success.
The increasing body of literature describing the role of host factors in COVID-19 pathogenesis demonstrates the need to combine diverse, multi-omic data to evaluate and substantiate the most robust ...evidence and inform development of therapies. Here we present a dynamic ranking of host genes implicated in human betacoronavirus infection (SARS-CoV-2, SARS-CoV, MERS-CoV, seasonal coronaviruses). We conducted an extensive systematic review of experiments identifying potential host factors. Gene lists from diverse sources were integrated using Meta-Analysis by Information Content (MAIC). This previously described algorithm uses data-driven gene list weightings to produce a comprehensive ranked list of implicated host genes. From 32 datasets, the top ranked gene was PPIA, encoding cyclophilin A, a druggable target using cyclosporine. Other highly-ranked genes included proposed prognostic factors (CXCL10, CD4, CD3E) and investigational therapeutic targets (IL1A) for COVID-19. Gene rankings also inform the interpretation of COVID-19 GWAS results, implicating FYCO1 over other nearby genes in a disease-associated locus on chromosome 3. Researchers can search and review the gene rankings and the contribution of different experimental methods to gene rank at https://baillielab.net/maic/covid19 . As new data are published we will regularly update the list of genes as a resource to inform and prioritise future studies.
The dynamic genome of Hydra Rokhsar, Daniel S; Steele, Robert E; Chapman, Jarrod A ...
Nature (London),
03/2010, Letnik:
464, Številka:
7288
Journal Article
Recenzirano
Odprti dostop
The freshwater cnidarian Hydra was first described in 1702 and has been the object of study for 300 years. Experimental studies of Hydra between 1736 and 1744 culminated in the discovery of asexual ...reproduction of an animal by budding, the first description of regeneration in an animal, and successful transplantation of tissue between animals. Today, Hydra is an important model for studies of axial patterning, stem cell biology and regeneration. Here we report the genome of Hydra magnipapillata and compare it to the genomes of the anthozoan Nematostella vectensis and other animals. The Hydra genome has been shaped by bursts of transposable element expansion, horizontal gene transfer, trans-splicing, and simplification of gene structure and gene content that parallel simplification of the Hydra life cycle. We also report the sequence of the genome of a novel bacterium stably associated with H. magnipapillata. Comparisons of the Hydra genome to the genomes of other animals shed light on the evolution of epithelia, contractile tissues, developmentally regulated transcription factors, the Spemann-Mangold organizer, pluripotency genes and the neuromuscular junction.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, ...and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Coordination of a number of molecular mechanisms including transcription, alternative splicing, and class switch recombination are required to facilitate development, activation, and survival of B ...cells. Disruption of these pathways can result in malignant transformation. Recently, next-generation sequencing has identified a number of novel mutations in mantle cell lymphoma (MCL) patients including mutations in the ubiquitin E3 ligase UBR5. Approximately 18% of MCL patients were found to have mutations in UBR5, with the majority of mutations within the HECT domain of the protein that can accept and transfer ubiquitin molecules to the substrate. Determining if UBR5 controls the maturation of B cells is important to fully understand malignant transformation to MCL. To elucidate the role of UBR5 in B-cell maturation and activation, we generated a conditional mutant disrupting UBR5′s C-terminal HECT domain. Loss of the UBR5 HECT domain leads to a block in maturation of B cells in the spleen and upregulation of proteins associated with messenger RNA splicing via the spliceosome. Our studies reveal a novel role of UBR5 in B-cell maturation by stabilization of spliceosome components during B-cell development and suggests UBR5 mutations play a role in MCL transformation.
•Using a novel mouse model mimicking MCL patient mutations, the loss of HECT domain of UBR5 causes alterations in B-cell development.•UBR5 mutations lead to stabilization of UBR5 and spliceosome components.
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Iron pyrite (cubic FeS2) is a promising candidate absorber material for earth-abundant thin-film solar cells. Here, we report on phase-pure, large-grain, and uniform polycrystalline pyrite films that ...are fabricated by solution-phase deposition of an iron(III) acetylacetonate molecular ink followed by sequential annealing in air, H2S, and sulfur gas at temperatures up to 550 °C. Phase and elemental compositions of the films are characterized by conventional and synchrotron X-ray diffraction, Raman spectroscopy, Auger electron spectroscopy, secondary ion mass spectrometry, and X-ray photoelectron spectroscopy (XPS). These solution-deposited films have more oxygen and alkalis, less carbon and hydrogen, and smaller optical band gaps (E g = 0.87 ± 0.05 eV) than similar films made by chemical vapor deposition. XPS is used to assess the chemical composition of the film surface before and after exposure to air and immersion in water to remove surface contaminants. Optical measurements of films rich in marcasite (orthorhombic FeS2) show that marcasite has a band gap at least as large as pyrite and that the two polymorphs share similar absorptivity spectra, in excellent agreement with density functional theory models. Regardless of the marcasite and elemental impurity contents, all films show p-type, weakly activated transport with curved Arrhenius plots, a room-temperature resistivity of ∼1 Ω cm, and a hole mobility that is too small to measure by Hall effect. This universal electrical behavior strongly suggests that a common defect or a hole-rich surface layer governs the electrical properties of most FeS2 thin films.
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