Quantitative imaging workshop XIX: Utilizing quantitative thoracic imaging to optimize population health final summary.

Lung cancer screening involves the use of thoracic CT for both detection and measurements of suspicious lung nodules to guide the screening management. Since lung cancer screening eligibility typically requires age over 50 years along with >20 pack-year tobacco exposure, thoracic CT scans also frequently reveal evidence for pulmonary emphysema as well as coronary artery calcification. These three thoracic diseases are collectively three of the leading causes of premature death across the world. Screening for the major thoracic diseases in this heavily tobacco-exposed cohort is broadening the focus of lung cancer screening to a more comprehensive health evaluation including discussing the relevance of screen-detected findings of the heart and lung parenchyma. The status and implications of these emerging issues were reviewed in a multidisciplinary workshop focused on the process of quantitative imaging in the lung cancer screening setting to guide the evolution of this important new area of public health.

Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association.

The application of next-generation sequencing (NGS) to clinical practice is still hampered by the ability to interpret the clinical relevance of novel variants and the difficulty of evaluating their effect in specific tissues. Here, we applied integrated genomic approaches for interrogating blood samples of two unrelated individuals with neurodevelopmental disorders and identified a novel neuro-pathogenic role for the Mitogen-Activated Protein Kinase 4 gene (MAP4K4). In particular, we identified two novel frameshift variants in coding exons expressed in the blood and neuronal isoforms. Both variants were predicted to generate non-sense-mediated decay. By transcriptome analysis, we simultaneously demonstrated the deleterious effect of the identified variants on the splicing activity and stability of MAP4K4 mRNA. Therefore, we propose MAP4K4 as a novel causative gene for non-syndromic and syndromic neurodevelopmental disorders. Altogether, we prove the efficacy of an integrated approach of exome and transcriptome sequencing in the resolution of undiagnosed cases by leveraging the analysis of variants in genes expressed in peripheral blood.

Trifluoromethylation of Carbonyl and Unactivated Olefin Derivatives by C(sp3 )-C Bond Cleavage.

Herein, we report a Cu-mediated trifluoromethylation of carbonyl-type compounds and unactivated olefins enabled by visible-light irradiation via σ C(sp3 )-C bond-functionalization. The reaction is distinguished by its modularity, mild conditions and wide scope-even in the context of late-stage functionalization-thus offering a complementary approach en route to valuable C(sp3 )-CF3 architectures from easily accessible precursors.

Catalytic Photoinduced Intramolecular Decarboxylative and Desulfonylative sp3 Allylation Enabled by Sulfinate Salts.

Herein, we describe a catalytic intramolecular decarboxylative/desulfonylative sp3 allylation triggered by sulfinate salts under light irradiation. The reaction is likely enabled by a non-classical, radical-polar crossover mechanism, allowing rapid and reliable access to valuable allyl architectures from readily accessible precursors. The protocol is characterized by its operational simplicity and scalability, employing abundant, commercially available catalysts.

Decarboxylative Conjunctive Cross-coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis.

The synthesis of complex alkyl boronic esters through conjunctive cross-coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross-coupling cascade of vinyl boronic esters. Excellent functional-group tolerance is displayed, and application of a range of carboxylic acids, including secondary α-amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross-coupling was also applied to the synthesis of sedum alkaloids.

Site-Selective 1,2-Dicarbofunctionalization of Vinyl Boronates through Dual Catalysis.

A modular, site-selective 1,2-dicarbofunctionalization of vinyl boronates with organic halides through dual catalysis is described. This reaction proceeds under mild conditions and is characterized by excellent chemo- and regioselectivity. It thus represents a complementary new technique for preparing densely functionalized alkyl boron architectures from simple and accessible precursors.

Synthesis of Functionalized Cyclopropanes from Carboxylic Acids by a Radical Addition-Polar Cyclization Cascade.

Herein, we describe the development of a photoredox-catalyzed decarboxylative radical addition-polar cyclization cascade approach to functionalized cyclopropanes. Reductive termination of radical-polar crossover reactions between aliphatic carboxylic acids and electron-deficient alkenes yielded carbanion intermediates that were intercepted in intramolecular alkylations with alkyl chlorides appended to the alkene substrate. The mild conditions, which make use of a readily available organic photocatalyst and visible light, were demonstrated to be amenable to a broad range of structurally complex carboxylic acids and a wide variety of chloroalkyl alkenes, demonstrating exquisite functional group tolerance.

Visible-Light-Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ-Amino Boronic Esters.

The synthesis of alkyl boronic esters by direct decarboxylative radical addition of carboxylic acids to vinyl boronic esters is described. The reaction proceeds under mild photoredox catalysis and involves an unprecedented single-electron reduction of an α-boryl radical intermediate to the corresponding anion. The reaction is amenable to a diverse range of substrates, including α-amino, α-oxy, and alkyl carboxylic acids, thus providing a novel method to rapidly access boron-containing molecules of potential biological importance.

Impairment of F1F0-ATPase, adenine nucleotide translocator and adenylate kinase causes mitochondrial energy deficit in human skin fibroblasts with chromosome 21 trisomy.

A central role for mitochondrial dysfunction has been proposed in the pathogenesis of DS (Down's syndrome), a multifactorial disorder caused by trisomy of human chromosome 21. To explore whether and how abnormalities in mitochondrial energy metabolism are involved in DS pathogenesis, we investigated the catalytic properties, gene expression and protein levels of certain proteins involved in mitochondrial ATP synthesis, such as F1F0-ATPase, ANT (adenine nucleotide translocator) and AK (adenylate kinase), in DS-HSF (human skin fibroblasts with trisomic karyotype), comparing them with euploid fibroblasts. In DS-HSF, we found a strong impairment of mitochondrial ATP synthesis due to a reduction in the catalytic efficiency of each of the investigated proteins. This impairment occurred in spite of unchanged gene expression and an increase in ANT and AK protein content, whereas the amount of ATPase subunits was selectively reduced. Interestingly, exposure of DS-HSF to dibutyryl-cAMP, a permanent derivative of cAMP, stimulated ANT, AK and ATPase activities, whereas H89, a specific PKA (protein kinase A) inhibitor, suppressed this cAMPdependent activation, indicating an involvement of the cAMP/PKA-mediated signalling pathway in the ATPase, ANT and AK deficit. Consistently, DS-HSF showed decreased basal levels of cAMP and reduced PKA activity. Despite the impairment of mitochondrial energy apparatus, no changes in cellular energy status, but increased basal levels of L-lactate, were found in DS-HSF, which partially offset for the mitochondrial energy deficit by increasing glycolysis and mitochondrial mass.These results provide new insight into the molecular basis for mitochondrial dysfunction in DS and might provide a molecular explanation for some clinical features of the syndrome.

Hunter-Gatherers in context: Mammal community composition in a northern Tanzania landscape used by Hadza foragers and Datoga pastoralists.

In many regions of sub Saharan Africa large mammals occur in human-dominated areas, yet their community composition and abundance have rarely been described in areas occupied by traditional hunter-gatherers and pastoralists. Surveys of mammal populations in such areas provide important measures of biodiversity and provide ecological context for understanding hunting practices. Using a sampling grid centered on a Hadza hunter-gatherer camp and covering 36 km2 of semi-arid savannah in northern Tanzania, we assessed mammals using camera traps (n = 19 stations) for c. 5 months (2,182 trap nights). In the study area (Tli'ika in the Hadza language), we recorded 36 wild mammal species. Rarefaction curves suggest that sampling effort was sufficient to capture mammal species richness, yet some species known to occur at low densities in the wider area (e.g. African lions, wildebeest) were not detected. Relative abundance indices of wildlife species varied by c. three orders of magnitude, from a mean of 0.04 (African wild dog) to 20.34 capture events per 100 trap-nights (Kirk's dik dik). To contextualize the relative abundance of wildlife in the study area, we compared our study's data to comparable camera trap data collected in a fully protected area of northern Tanzania with similar rainfall (Lake Manyara National Park). Raw data and negative binomial regression analyses show that wild herbivores and wild carnivores were generally detected in the national park at higher rates than in the Hadza-occupied region. Livestock were notably absent from the national park, but were detected at high levels in Tli'ika, and cattle was the second most frequently detected species in the Hadza-used area. We discuss how these data inform current conservation efforts, studies of Hadza hunting, and models of hunter-gatherer foraging ecology and diet.

Proteasome function is required for activation of programmed cell death in heat shocked tobacco Bright-Yellow 2 cells.

To find out whether and how proteasome is involved in plant programmed cell death (PCD) we measured proteasome function in tobacco cells undergoing PCD as a result of heat shock (HS-PCD). Reactive oxygen species (ROS) production, cytochrome c levels and caspase-3-like protease activation were also measured in the absence or presence of MG132, a proteasome inhibitor. We show that proteasome activation occurs in early phase of HS-PCD upstream of the caspase-like proteases activation; moreover inhibition of proteasome function by MG132 results in prevention of PCD perhaps due to the prevention of ROS production, cytochrome c release and caspase-3-like protease activation.

A computational search for box C/D snoRNA genes in the Drosophila melanogaster genome.

MOTIVATION: In eukaryotes, the family of non-coding RNA genes includes a number of genes encoding small nucleolar RNAs (mainly C/D and H/ACA snoRNAs), which act as guides in the maturation or post-transcriptional modifications of target RNA molecules. Since in Drosophila melanogaster (Dm) only few examples of snoRNAs have been identified so far by cDNA libraries screening, integration of the molecular data with in silico identification of these types of genes could throw light on their organization in the Dm genome. RESULTS: We have performed a computational screening of the Dm genome for C/D snoRNA genes, followed by experimental validation of the putative candidates. Few of the 26 confirmed snoRNAs had been recognized by cDNA library analysis. Organization of the Dm genome was also found to be more variegated than previously suspected, with snoRNA genes nested in both the introns and exons of protein-coding genes. This finding suggests that the presence of additional mechanisms of snoRNA biogenesis based on the alternative production of overlapping mRNA/snoRNA molecules. AVAILABILITY: Additional information is available at http://www.bioinformatica.unito.it/bioinformatics/snoRNAs.