Iterative reconstruction of a global metabolic model of Acinetobacter baylyi ADP1 using high-throughput growth phenotype and gene essentiality data

<p>Abstract</p> <p>Background</p> <p>Genome-scale metabolic models are powerful tools to study global properties of metabolic networks. They provide a way to integrate various types of biological information in a single framework, providing a structured representation of available knowledge on the metabolism of the respective species.</p> <p>Results</p> <p>We reconstructed a constraint-based metabolic model of <it>Acinetobacter baylyi </it>ADP1, a soil bacterium of interest for environmental and biotechnological applications with large-spectrum biodegradation capabilities. Following initial reconstruction from genome annotation and the literature, we iteratively refined the model by comparing its predictions with the results of large-scale experiments: (1) high-throughput growth phenotypes of the wild-type strain on 190 distinct environments, (2) genome-wide gene essentialities from a knockout mutant library, and (3) large-scale growth phenotypes of all mutant strains on 8 minimal media. Out of 1412 predictions, 1262 were initially consistent with our experimental observations. Inconsistencies were systematically examined, leading in 65 cases to model corrections. The predictions of the final version of the model, which included three rounds of refinements, are consistent with the experimental results for (1) 91% of the wild-type growth phenotypes, (2) 94% of the gene essentiality results, and (3) 94% of the mutant growth phenotypes. To facilitate the exploitation of the metabolic model, we provide a web interface allowing online predictions and visualization of results on metabolic maps.</p> <p>Conclusion</p> <p>The iterative reconstruction procedure led to significant model improvements, showing that genome-wide mutant phenotypes on several media can significantly facilitate the transition from genome annotation to a high-quality model.</p

A complete collection of single-gene deletion mutants of Acinetobacter baylyi ADP1

We have constructed a collection of single-gene deletion mutants for all dispensable genes of the soil bacterium Acinetobacter baylyi ADP1. A total of 2594 deletion mutants were obtained, whereas 499 (16%) were not, and are therefore candidate essential genes for life on minimal medium. This essentiality data set is 88% consistent with the Escherichia coli data set inferred from the Keio mutant collection profiled for growth on minimal medium, while 80% of the orthologous genes described as essential in Pseudomonas aeruginosa are also essential in ADP1. Several strategies were undertaken to investigate ADP1 metabolism by (1) searching for discrepancies between our essentiality data and current metabolic knowledge, (2) comparing this essentiality data set to those from other organisms, (3) systematic phenotyping of the mutant collection on a variety of carbon sources (quinate, 2-3 butanediol, glucose, etc.). This collection provides a new resource for the study of gene function by forward and reverse genetic approaches and constitutes a robust experimental data source for systems biology approaches

SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

Cytogenetic Prognostication Within Medulloblastoma Subgroups

PURPOSE: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. PATIENTS AND METHODS: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. RESULTS: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. CONCLUSION: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials

Voie historique de Paris aux Ardennes de César à de Gaulle / Marcel Fèvre

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MIRI/JWST observations reveal an extremely obscured starburst in the z = 6.9 system SPT0311-58

Luminous infrared starbursts in the early Universe are thought to be the progenitors of massive quiescent galaxies identified at redshifts 2- 4. Using the Mid-IRfrared Instrument (MIRI) on board the James Webb Space Telescope (JWST), we present mid-infrared sub-arcsec imaging and spectroscopy of such a starburst: the slightly lensed hyper-luminous infrared system SPT0311-58 at z = 6.9. The MIRI IMager (MIRIM) and Medium Resolution Spectrometer (MRS) observations target the stellar (rest-frame 1.26 μm emission) structure and ionised (Paα and Hα) medium on kpc scales in the system. The MIRI observations are compared with existing ALMA far-infrared continuum and [C II]158μm imaging at a similar angular resolution. Even though the ALMA observations imply very high star formation rates (SFRs) in the eastern (E) and western (W) galaxies of the system, the Hα line is, strikingly, not detected in our MRS observations. This fact, together with the detection of the ionised gas phase in Paα, implies very high internal nebular extinction with lower limits (AV) of 4.2 (E) and 3.9 mag (W) as well as even larger values (5.6 (E) and 10.0 (W)) by spectral energy distribution (SED) fitting analysis. The extinction-corrected Paα lower limits of the SFRs are 383 and 230 M⊙ yr-1 for the E and W galaxies, respectively. This represents 50% of the SFRs derived from the [C II]158 μm line and infrared light for the E galaxy and as low as 6% for the W galaxy. The MIRIM observations reveal a clumpy stellar structure, with each clump having 3- 5× 109 M⊙ mass in stars, leading to a total stellar mass of 2.0 and 1.5× 1010 M⊙ for the E and W galaxies, respectively. The specific star formation (sSFR) in the stellar clumps ranges from 25 to 59 Gyr-1, assuming a star formation with a 50- 100 Myr constant rate. This sSFR is three to ten times larger than the values measured in galaxies of similar stellar mass at redshifts 6- 8. Thus, SPT0311-58 clearly stands out as a starburst system when compared with typical massive star-forming galaxies at similar high redshifts. The overall gas mass fraction is Mgas/M∗ ∼ 3, similar to that of z ∼ 4.5- 6 star-forming galaxies, suggesting a flattening of the gas mass fraction in massive starbursts up to redshift 7. The kinematics of the ionised gas in the E galaxy agrees with the known [C II] gas kinematics, indicating a physical association between the ionised gas and the cold ionised or neutral gas clumps. The situation in the W galaxy is more complex, as it appears to be a velocity offset by about +700 km s-1 in the Paα relative to the [C II] emitting gas. The nature of this offset and its reality are not fully established and require further investigation. The observed properties of SPT0311-58, such as the clumpy distribution at sub(kpc) scales and the very high average extinction, are similar to those observed in low- and intermediate-z luminous (E galaxy) and ultra-luminous (W galaxy) infrared galaxies, even though SPT0311-58 is observed only ∼800 Myr after the Big Bang. Such massive, heavily obscured clumpy starburst systems as SPT0311-58 likely represent the early phases in the formation of a massive high-redshift bulge, spheroids and/or luminous quasars. This study demonstrates that MIRI and JWST are, for the first time, able to explore the rest-frame near-infrared stellar and ionised gas structure of these galaxies, even during the Epoch of Reionization.ISSN:0004-6361ISSN:1432-074

Papillary tumor of the pineal region : A distinct molecular entity

Papillary tumor of the pineal region (PTPR) is a neuroepithelial brain tumor, which might pose diagnostic difficulties and recurs often. Little is known about underlying molecular alterations. We therefore investigated chromosomal copy number alterations, DNA methylation patterns and mRNA expression profiles in a series of 24 PTPRs. Losses of chromosome 10 were identified in all 13 PTPRs examined. Losses of chromosomes 3 and 22q (54%) as well as gains of chromosomes 8p (62%) and 12 (46%) were also common. DNA methylation profiling using Illumina 450k arrays reliably distinguished PTPR from ependymomas and pineal parenchymal tumors of intermediate differentiation. PTPR could be divided into two subgroups based on methylation pattern, PTPR group 2 showing higher global methylation and a tendency toward shorter progression-free survival (P = 0.06). Genes overexpressed in PTPR as compared with ependymal tumors included SPDEF, known to be expressed in the rodent subcommissural organ. Notable SPDEF protein expression was encountered in 15/19 PTPRs as compared with only 2/36 ependymal tumors, 2/19 choroid plexus tumors and 0/23 samples of other central nervous system (CNS) tumor entities. In conclusion, PTPRs show typical chromosomal alterations as well as distinct DNA methylation and expression profiles, which might serve as useful diagnostic tools

Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy

Les approches écosystémiques de la santé dans la francophonie

Ce numéro spécial de [VertigO] – La revue électronique en science de l'environnement « Les approches écosystémiques de la santé dans la francophonie » présente différents écrits (articles, essais et billets) sur la pratique des approches écosystémiques de la santé à travers la présentation de ses défis, ses réalités et ses réalisations. Peu de publications valorisant l’apport important des francophones à ce courant ont été développées. Ce numéro spécial vise donc à offrir des publications en français qui permettront une meilleure diffusion de ces approches. Ce projet a été entrepris par la section Québec-Acadie-Atlantique de la Communauté de pratique canadienne sur les approches écosystémiques de la santé (CoPEH-Canada) en collaboration avec la Communauté de pratique Écosanté pour l’Afrique de l’Ouest et du centre (CoPES-AOC), le Groupe de recherche en épidémiologie des zoonoses et santé publique (GREZOSP) et l’École des Hautes Études en santé publique (EHESP) de Rennes