Ultrafast light-induced response of photoactive yellow protein chromophore analogues

The fluorescence decays of several analogues of the photoactive yellow protein (PYP) chromophore in aqueous solution have been measured by femtosecond fluorescence up-conversion and the corresponding time-resolved fluorescence spectra have been reconstructed. The native chromophore of PYP is a thioester derivative of p-coumaric acid in its trans deprotonated form. Fluorescence kinetics are reported for a thioester phenyl analogue and for two analogues where the thioester group has been changed to amide and carboxylate groups. The kinetics are compared to those we previously reported for the analogues bearing ketone and ester groups. The fluorescence decays of the full series are found to lie in the 1–10 ps range depending on the electron-acceptor character of the substituent, in good agreement with the excited-state relaxation kinetics extracted from transient absorption measurements. Steady-state photolysis is also examined and found to depend strongly on the nature of the substituent. While it has been shown that the ultrafast light-induced response of the chromophore in PYP is controlled by the properties of the protein nanospace, the present results demonstrate that, in solution, the relaxation dynamics and pathway of the chromophore is controlled by its electron donor–acceptor structure: structures of stronger electron donor–acceptor character lead to faster decays and less photoisomerisation

Dynamic Risk Prediction of 30-Day Mortality in Patients With Advanced Lung Cancer:Comparing Five Machine Learning Approaches

International audiencePURPOSE Administering systemic anticancer treatment (SACT) to patients near death can negatively affect their health-related quality of life. Late SACT administrations should be avoided in these cases. Machine learning techniques could be used to build decision support tools leveraging registry data for clinicians to limit late SACT administration. MATERIALS AND METHODS Patients with advanced lung cancer who were treated at the Department of Oncology, Aalborg University Hospital and died between 2010 and 2019 were included (N = 2,368). Diagnoses, treatments, biochemical data, and histopathologic results were used to train predictive models of 30-day mortality using logistic regression with elastic net penalty, random forest, gradient tree boosting, multilayer perceptron, and long short-term memory network. The importance of the variables and the clinical utility of the models were evaluated. RESULTS The random forest and gradient tree boosting models outperformed other models, whereas the artificial neural network–based models underperformed. Adding summary variables had a modest effect on performance with an increase in average precision from 0.500 to 0.505 and from 0.498 to 0.509 for the gradient tree boosting and random forest models, respectively. Biochemical results alone contained most of the information with a limited degradation of the performances when fitting models with only these variables. The utility analysis showed that by applying a simple threshold to the predicted risk of 30-day mortality, 40% of late SACT administrations could have been prevented at the cost of 2% of patients stopping their treatment 90 days before death. CONCLUSION This study demonstrates the potential of a decision support tool to limit late SACT administration in patients with cancer. Further work is warranted to refine the model, build an easy-to-use prototype, and conduct a prospective validation study

VEB-1 in Achromobacter xylosoxidans from Cystic Fibrosis Patient, France

Multidrug-resistant Achromobacter xylosoxidans was recovered from the sputum of a patient with cystic fibrosis. The VEB-1 extended-spectrum β-lactamase was detected on a class 1 integron. This first report of a VEB-1–producing isolate in this population requires further investigation to determine its distribution

Mineralogical and hydrogeological study of "pouhons" in the lower Palaeozoic formations of the Stavelot-Venn Massif, Belgium

peer reviewedNumer ous natur ally CO 2-rich mineral water springs, locally called pouhons, occur in the Stavelot-Venn Massif. These water springs show a particular composition with a high content of iron, manganese and lithium, and are characterised by a redorange colour resulting from iron hydroxide precipitation near the land surface. Radon measurements have shown that these ferruginous deposits are weakly radioactive. The Upper Cambrian black shales of the La Gleize Formation are also known to display radioactive anomalies. These rocks show enrichment in HFSE (Pb, U, Y, Ce, Zr, Ti, Nb) and are depleted in transition metals (Co, Ni, Cu, Zn). Specific minerals such as florencite-(Ce), monazite-(Ce), xenotime-(Y) and zircon have been identified and are probably at the origin of the radioactive anomalies. Uranium was gradually leached from these minerals, transported in solution, and finally concentrated in ferruginous muds. These muds are mainly composed of goethite (most often amorphous), residual quartz and calcite in some samples. The most probable hypothesis is that uranium is adsorbed in small concentrations on the goethite surface. On the other hand, the Ottré Formation (Ordovician) appears to be the main source of lithium, iron and manganese. Pouhon waters have therefore probably leached rocks of various mineralogy and chemical composition during their sub-surface circulation

Synthesis and antibacterial activities of cadiolides A, B and C and analogues

The one-pot multicomponent synthesis of natural butenolides named cadiolides A, B, C and analogues has been realized. The antibacterial structure activity relationship shows that the presence of phenolic hydroxyl groups and the number and position of bromine atoms on the different aromatic rings are important features for antibacterial activity, besides it was demonstrated the tolerance of both benzene and furan ring at position 3 of the butenolide nucleus. Furthermore, none of the most relevant antibacterial compounds showed any cytotoxicity in freshly isolated human neutrophils

Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer

International audienceBackground: A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated. Methods: Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levelsrelated breast tumours. Results: We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct. Conclusion: Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper-but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors

Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution

Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 ‘multihit’ HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML. Through analysis of serial samples, antecedent TP53-heterozygous clones and in vivo perturbations, we demonstrate a hitherto unrecognized effect of chronic inflammation, which suppressed TP53 WT HSPCs while enhancing the fitness advantage of TP53-mutant cells and promoted genetic evolution. Our findings will facilitate the development of risk-stratification, early detection and treatment strategies for TP53-mutant leukemia, and are of broad relevance to other cancer types

A New Multidisciplinary Home Care Telemedicine System to Monitor Stable Chronic Human Immunodeficiency Virus-Infected Patients: A Randomized Study

BACKGROUND: Antiretroviral therapy has changed the natural history of human immunodeficiency virus (HIV) infection in developed countries, where it has become a chronic disease. This clinical scenario requires a new approach to simplify follow-up appointments and facilitate access to healthcare professionals. METHODOLOGY: We developed a new internet-based home care model covering the entire management of chronic HIV-infected patients. This was called Virtual Hospital. We report the results of a prospective randomised study performed over two years, comparing standard care received by HIV-infected patients with Virtual Hospital care. HIV-infected patients with access to a computer and broadband were randomised to be monitored either through Virtual Hospital (Arm I) or through standard care at the day hospital (Arm II). After one year of follow up, patients switched their care to the other arm. Virtual Hospital offered four main services: Virtual Consultations, Telepharmacy, Virtual Library and Virtual Community. A technical and clinical evaluation of Virtual Hospital was carried out. FINDINGS: Of the 83 randomised patients, 42 were monitored during the first year through Virtual Hospital (Arm I) and 41 through standard care (Arm II). Baseline characteristics of patients were similar in the two arms. The level of technical satisfaction with the virtual system was high: 85% of patients considered that Virtual Hospital improved their access to clinical data and they felt comfortable with the videoconference system. Neither clinical parameters [level of CD4+ T lymphocytes, proportion of patients with an undetectable level of viral load (p = 0.21) and compliance levels >90% (p = 0.58)] nor the evaluation of quality of life or psychological questionnaires changed significantly between the two types of care. CONCLUSIONS: Virtual Hospital is a feasible and safe tool for the multidisciplinary home care of chronic HIV patients. Telemedicine should be considered as an appropriate support service for the management of chronic HIV infection. TRIAL REGISTRATION: Clinical-Trials.gov: NCT01117675

Cancer screening in a middle-aged general population: factors associated with practices and attitudes

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to identify factors associated with cancer screening practices and with general attitudes toward cancer screening in a general population.</p> <p>Methods</p> <p>Mailed survey of 30–60 year old residents of Geneva, Switzerland, that included questions about screening for five cancers (breast, cervix uteri, prostate, colon, skin) in the past 3 years, attitudes toward screening, health care use, preventive behaviours and socio-demographic characteristics. Cancer screening practice was dichotomised as having done at least one screening test in the past 3 years versus none.</p> <p>Results</p> <p>The survey response rate was 49.3% (2301/4670). More women than men had had at least one cancer screening test in the past 3 years (83.2% vs 34.5%, p < 0.001). A majority of women had had a cervical smear (76.6%) and a mammography (age 30–49: 35.0%; age 50 and older: 90.3%); and 55.1% of men 50–60 years old had been screened for prostate cancer. Other factors associated with screening included older age, higher income, a doctor visit in the past 6 months, reporting a greater number of preventive behaviours and a positive attitude toward screening. Factors linked with positive attitudes included female gender, higher level of education, gainful employment, higher income, a doctor visit in the past 6 months and a personal history of cancer.</p> <p>Conclusion</p> <p>Attitudes play an important role in cancer screening practices among middle-aged adults in the general population, independent of demographic variables (age and sex) that determine in part screening recommendations. Negative attitudes were the most frequent among men and the most socio-economically disadvantaged. The moderate participation rate raises the possibility of selection bias.</p

Histone Methylation by NUE, a Novel Nuclear Effector of the Intracellular Pathogen Chlamydia trachomatis

Sequence analysis of the genome of the strict intracellular pathogen Chlamydia trachomatis revealed the presence of a SET domain containing protein, proteins that primarily function as histone methyltransferases. In these studies, we demonstrated secretion of this protein via a type III secretion mechanism. During infection, the protein is translocated to the host cell nucleus and associates with chromatin. We therefore named the protein nuclear effector (NUE). Expression of NUE in mammalian cells by transfection reconstituted nuclear targeting and chromatin association. In vitro methylation assays confirmed NUE is a histone methyltransferase that targets histones H2B, H3 and H4 and itself (automethylation). Mutants deficient in automethylation demonstrated diminished activity towards histones suggesting automethylation functions to enhance enzymatic activity. Thus, NUE is secreted by Chlamydia, translocates to the host cell nucleus and has enzymatic activity towards eukaryotic substrates. This work is the first description of a bacterial effector that directly targets mammalian histones