Gene regulation during cell-cycle progression is an intricately choreographed process, ensuring accurate DNA replication and division. However, the translational landscape of gene expression ...underlying cell-cycle progression remains largely unknown. Employing genome-wide ribosome profiling, we uncover widespread translational regulation of hundreds of mRNAs serving as an unexpected mechanism for gene regulation underlying cell-cycle progression. A striking example is the S phase translational regulation of RICTOR, which is associated with cell cycle-dependent activation of mammalian target of rapamycin complex 2 (mTORC2) signaling and accurate cell-cycle progression. We further identified unappreciated coordination in translational control of mRNAs within molecular complexes dedicated to cell-cycle progression, lipid metabolism, and genome integrity. This includes the majority of mRNAs comprising the cohesin and condensin complexes responsible for maintaining genome organization, which are coordinately translated during specific cell cycle phases via their 5′ UTRs. Our findings illuminate the prevalence and dynamic nature of translational regulation underlying the mammalian cell cycle.
It remains unknown to what extent consensus molecular subtype (CMS) groups and immune-stromal infiltration patterns improve our ability to predict outcomes over tumor–node–metastasis (TNM) staging ...and microsatellite instability (MSI) status in early-stage colorectal cancer (CRC).
We carried out a comprehensive retrospective biomarker analysis of prognostic markers in adjuvant chemotherapy-untreated (N = 1656) and treated (N = 980), stage II (N = 1799) and III (N = 837) CRCs. We defined CMS scores and estimated CD8+ cytotoxic lymphocytes (CytoLym) and cancer-associated fibroblasts (CAF) infiltration scores from bulk tumor tissue transcriptomes (CMSclassifier and MCPcounter R packages); constructed a stratified multivariable Cox model for disease-free survival (DFS); and calculated the relative proportion of explained variation by each marker (clinicopathological ClinPath, genomics Gen: MSI, BRAF and KRAS mutations, CMS scores CMS and microenvironment cells MicroCells: CytoLym+CAF).
In multivariable models, only ClinPath and MicroCells remained significant prognostic factors, with both CytoLym and CAF infiltration scores improving survival prediction beyond other markers. The explained variation for DFS models of ClinPath, MicroCells, Gen markers and CMS4 scores was 77%, 14%, 5.3% and 3.7%, respectively, in stage II; and 55.9%, 35.1%, 4.1% and 0.9%, respectively, in stage III. Patients whose tumors were CytoLym high/CAF low had better DFS than other strata HR=0.71 (0.6–0.9); P = 0.004. Microsatellite stable tumors had the strongest signal for improved outcomes with CytoLym high scores (interaction P = 0.04) and the poor prognosis linked to high CAF scores was limited to stage III disease (interaction P = 0.04).
Our results confirm that tumor microenvironment infiltration patterns represent potent determinants of the risk for distant dissemination in early-stage CRC. Multivariable models suggest that the prognostic value of MSI and CMS groups is largely explained by CytoLym and CAF infiltration patterns.
Cancer cells must integrate multiple biosynthetic demands to drive indefinite proliferation. How these key cellular processes, such as metabolism and protein synthesis, crosstalk to fuel cancer cell ...growth is unknown. Here, we uncover the mechanism by which the Myc oncogene coordinates the production of the two most abundant classes of cellular macromolecules, proteins, and nucleic acids in cancer cells. We find that a single rate-limiting enzyme, phosphoribosyl-pyrophosphate synthetase 2 (PRPS2), promotes increased nucleotide biosynthesis in Myc-transformed cells. Remarkably, Prps2 couples protein and nucleotide biosynthesis through a specialized cis-regulatory element within the Prps2 5′ UTR, which is controlled by the oncogene and translation initiation factor eIF4E downstream Myc activation. We demonstrate with a Prps2 knockout mouse that the nexus between protein and nucleotide biosynthesis controlled by PRPS2 is crucial for Myc-driven tumorigenesis. Together, these studies identify a translationally anchored anabolic circuit critical for cancer cell survival and an unexpected vulnerability for “undruggable” oncogenes, such as Myc.
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•Protein synthesis and nucleotide metabolism are coupled downstream of Myc•Translational control of Prps2 integrates nucleotide metabolism and protein synthesis•Loss of function of PRPS2, but not of PRPS1, is synthetic lethal upon Myc overexpression•Prps2 is dispensable for normal physiology but is essential for Myc-driven lymphoma
Elevated translation of a nucleotide biosynthesis enzyme proves to be a key nexus coordinating protein and nucleic acid synthesis in MYC-transformed cells, thereby revealing a vulnerability for “undruggable” oncogenes.
Pseudomonas syringae pv. actinidiae is a reemerging pathogen which causes bacterial canker of kiwifruit (Actinidia sp.). Since 2008, a global outbreak of P. syringae pv. actinidiae has occurred, and ...in 2010 this pathogen was detected in New Zealand. The economic impact and the development of resistance in P. syringae pv. actinidiae and other pathovars against antibiotics and copper sprays have led to a search for alternative management strategies. We isolated 275 phages, 258 of which were active against P. syringae pv. actinidiae. Extensive host range testing on P. syringae pv. actinidiae, other pseudomonads, and bacteria isolated from kiwifruit orchards showed that most phages have a narrow host range. Twenty-four were analyzed by electron microscopy, pulse-field gel electrophoresis, and restriction digestion. Their suitability for biocontrol was tested by assessing stability and the absence of lysogeny and transduction. A detailed host range was performed, phage-resistant bacteria were isolated, and resistance to other phages was examined. The phages belonged to the Caudovirales and were analyzed based on morphology and genome size, which showed them to be representatives of Myoviridae, Podoviridae, and Siphoviridae. Twenty-one Myoviridae members have similar morphologies and genome sizes yet differ in restriction patterns, host range, and resistance, indicating a closely related group. Nine of these Myoviridae members were sequenced, and each was unique. The most closely related sequenced phages were a group infecting Pseudomonas aeruginosa and characterized by phages JG004 and PAK_P1. In summary, this study reports the isolation and characterization of P. syringae pv. actinidiae phages and provides a framework for the intelligent formulation of phage biocontrol agents against kiwifruit bacterial canker.
Due to rapidly increasing world population and growing energy demands, the development of cleaner technologies to exploit renewable energy systems has become of primary importance in the collective ...efforts to reduce greenhouse gases emissions. The chemical conversion of renewable power into synthetic liquid fuels, such as methanol, allows an easier storage and transportation and avoids any fluctuating issues. Alternative process routes for methanol production other than from raw materials derived from fossil fuels have, during the past decade, grown in interest, where valorising the carbon capture and utilization concept and promoting synergies with the oil & gas industry are potentially achieved. The aim of this study is, in this regard, to investigate the sustainability aspects of alternative processes for synthetic methanol synthesis by applying a systematic methodology based on multi-criteria performance indicators (such as technological, economic, environmental and inherent safety). A total of eleven alternative methanol production schemes, based on synthetic methane or carbon dioxide transformation, are considered, analyzed and comparatively evaluated. The present results demonstrate that the process schemes using catalytic hydrogenation of carbon dioxide offers the best performance when considering a methanol capacity of 500 kg/h. A sensitivity analysis based on the Monte Carlo approach is also performed to verify the robustness of the results.
•The CH3OH as energy carrier for energy exploitation in remote areas.•The sustainability assessment of 11 alternative processes for CH3OH production.•The use of multi-criteria KPIs (technological, economic, environmental, inherent safety).•The catalytic hydrogenation of CO2 as the best option for production of CH3OH.•A possible integration of CH3OH in the existing fuel supply chains.
Cutaneous manifestation of COVID‐19 in images: a case report Avellana Moreno, R.; Estela Villa, L.M.; Avellana Moreno, V. ...
Journal of the European Academy of Dermatology and Venereology,
July 2020, Letnik:
34, Številka:
7
Journal Article
Tracing the source of metals in the environment is critical to understanding their pollution level and fate. Geologic materials are an important source of airborne particulate matter, but the ...contribution of contaminated soil to concentrations of Pb in airborne dust is not yet widely documented. To examine the potential significance of this mechanism, surface soil samples were collected, as well as wind-transported dust trapped at 1 and 2 m height at seven different locations including residential, industrial, high-traffic and rural sites. Samples of dust deposited on roofs from 24 schools were also obtained and analyzed for Pb isotope ratios.
Spatial distribution of Pb of airborne and sedimented dust suggests a process dominated by re-suspension/sedimentation, which was controlled by erosion, traffic and topography of the urban area. Anthropogenic lead input in the city grades outward the urban zone toward geogenic values. Our results shows that Pb-isotopic signatures of leaded gasoline are imprinted in dust sedimented on roofs. Considering that leaded-gasoline has not been in use in Mexico since two decades ago, this signature shows not only a Pb-legacy in soil, but also a re-suspension process affecting air column below 3 m in height. The combination of the 207Pb/206Pb data of the surrounding rocks and urban dust, reveal three well-defined zones with remarkable anthropogenic influence, which correspond to the oldest urban sectors. This work highlights the importance of spatial characterization of metals in particles suspended below a height of 3 m of the airborne column, a fact that should be considered to identify exposure paths to humans and the potential risks. Lead isotope signatures allowed the identification of geogenic and anthropogenic emission sources for dust, a matter that deserves consideration in the efforts to control airborne metal emissions.
► Lead isotopes identified geogenic an anthropogenic emission sources for dust. ► Leaded gasoline isotopic signatures are imprinted in sedimented dust from roofs. ► Lead distribution is controlled by erosion, traffic and topography. ► Three impacted areas are identified in oldest urbanized sectors.
Plant beneficial microbes mediate biocontrol of diseases by interfering with pathogens or via strengthening the host. Although phytohormones, including cytokinins, are known to regulate plant ...development and physiology as well as plant immunity, their production by microorganisms has not been considered as a biocontrol mechanism. Here we identify the ability of Pseudomonas fluorescens G20-18 to efficiently control P. syringae infection in Arabidopsis, allowing maintenance of tissue integrity and ultimately biomass yield. Microbial cytokinin production was identified as a key determinant for this biocontrol effect on the hemibiotrophic bacterial pathogen. While cytokinin-deficient loss-of-function mutants of G20-18 exhibit impaired biocontrol, functional complementation with cytokinin biosynthetic genes restores cytokinin-mediated biocontrol, which is correlated with differential cytokinin levels in planta. Arabidopsis mutant analyses revealed the necessity of functional plant cytokinin perception and salicylic acid-dependent defence signalling for this biocontrol mechanism. These results demonstrate microbial cytokinin production as a novel microbe-based, hormone-mediated concept of biocontrol. This mechanism provides a basis to potentially develop novel, integrated plant protection strategies combining promotion of growth, a favourable physiological status and activation of fine-tuned direct defence and abiotic stress resilience.
It has been suggested that intergenerational transmission of risk for substance use disorder (SUD) manifests in the brain anatomy of substance naïve adolescents. While volume and shapes of ...subcortical structures (SSS) have been shown to be heritable, these structures, especially the pallidum, putamen, nucleus accumbens, and hippocampus, have also been associated with substance use disorders. However, it is not clear if those anatomical differences precede substance use or are the result of that use. Therefore, we examined if volume and SSS of adolescents with a family history (FH+) of SUD differed from adolescents without such a history (FH−). Because risk for SUD is associated with anxiety and impulsivity, we also examined correlations between these psychological characteristics and volume/SSS. Using structural MRI and FSL software, we segmented subcortical structures and obtained indices of SSS and volumes of 64 FH+ and 58 FH− adolescents. We examined group differences in volume and SSS, and the correlations between volume/SSS and trait anxiety and impulsivity. FH+ adolescents had a significant inward deformation in the shape of the right anterior hippocampus compared to FH− adolescents, while the volume of this structure did not differ between groups. Neither shape nor volume of the other subcortical structures differed between groups. In the FH+ adolescents, the left hippocampus shape was positively correlated with both trait anxiety and impulsivity, while in FH− adolescents a negative correlation pattern of SSS was seen in the hippocampus. SSS appears to capture local anatomical features that traditional volumetric analysis does not. The inward shape deformation in the right anterior hippocampus in FH+ adolescents may be related to the known increased risk for behavioral dysregulation leading to SUD in FH+ offspring. Hippocampus shape also exhibits opposite patterns of correlation with anxiety and impulsivity scores across the FH+ and FH− adolescents. These novel findings may reveal neural correlates, not captured by traditional volumetric analysis, of familial transmission of increased vulnerability to SUD.
Shapes of subcortical structures capture local anatomical features that traditional volumetric analysis does not. The inward shape deformation in the right anterior hippocampus in the adolescents with a positive family history (FH+) of substance use disorder (SUD) may be related to the known increased risk for behavioral dysregulation leading to SUD in FH+ offspring.
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