Application of Cyclic Diaryliodonium Salts in the Synthesis of Axially Chiral Natural Product Analogues.

The application of cyclic diaryliodonium salts in the synthesis of bioactive natural product analogues was demonstrated. Axially chiral biaryls were obtained via the enantioselective ring opening of cyclic diaryliodonium salts. Regioselective borylation was key in accessing both enantiomers of a biphenol key intermediate in eight steps overall. 8,8″-Amino biflavones were synthesized, their bioactivity profiled, and the eutomer identified. The structure-activity relationship was probed.

The Golgi stacking protein GRASP55 is targeted by the natural compound prodigiosin.

BACKGROUND: The bacterial secondary metabolite prodigiosin has been shown to exert anticancer, antimalarial, antibacterial and immunomodulatory properties. With regard to cancer, it has been reported to affect cancer cells but not non-malignant cells, rendering prodigiosin a promising lead compound for anticancer drug discovery. However, a direct protein target has not yet been experimentally identified. METHODS: We used mass spectrometry-based thermal proteome profiling in order to identify target proteins of prodigiosin. For target validation, we employed a genetic knockout approach and electron microscopy. RESULTS: We identified the Golgi stacking protein GRASP55 as target protein of prodigiosin. We show that prodigiosin treatment severely affects Golgi morphology and functionality, and that prodigiosin-dependent cytotoxicity is partially reduced in GRASP55 knockout cells. We also found that prodigiosin treatment results in decreased cathepsin activity and overall blocks autophagic flux, whereas co-localization of the autophagosomal marker LC3 and the lysosomal marker LAMP1 is clearly promoted. Finally, we observed that autophagosomes accumulate at GRASP55-positive structures, pointing towards an involvement of an altered Golgi function in the autophagy-inhibitory effect of this natural compound. CONCLUSION: Taken together, we propose that prodigiosin affects autophagy and Golgi apparatus integrity in an interlinked mode of action involving the regulation of organelle alkalization and the Golgi stacking protein GRASP55. Video Abstract.

A X-linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria-like phenotypes.

APOO/MIC26 is a subunit of the MICOS complex required for mitochondrial cristae morphology and function. Here, we report a novel variant of the APOO/MIC26 gene that causes a severe mitochondrial disease with overall progeria-like phenotypes in two patients. Both patients developed partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies. The patients died at an early age of 12 or 18 months. Exome sequencing revealed a mutation (NM_024122.5): c.532G>T (p.E178*) in the APOO/MIC26 gene that causes a nonsense mutation leading to the loss of 20 C-terminal amino acids. This mutation resulted in a highly unstable and degradation prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells. We conclude that the novel mutation found in the APOO/MIC26 gene is a loss-of-function mutation impairing mitochondrial morphology and cristae morphogenesis.

Voice acoustics allow classifying autism spectrum disorder with high accuracy.

Early identification of children on the autism spectrum is crucial for early intervention with long-term positive effects on symptoms and skills. The need for improved objective autism detection tools is emphasized by the poor diagnostic power in current tools. Here, we aim to evaluate the classification performance of acoustic features of the voice in children with autism spectrum disorder (ASD) with respect to a heterogeneous control group (composed of neurotypical children, children with Developmental Language Disorder [DLD] and children with sensorineural hearing loss with Cochlear Implant [CI]). This retrospective diagnostic study was conducted at the Child Psychiatry Unit of Tours University Hospital (France). A total of 108 children, including 38 diagnosed with ASD (8.5 ± 0.25 years), 24 typically developing (TD; 8.2 ± 0.32 years) and 46 children with atypical development (DLD and CI; 7.9 ± 0.36 years) were enrolled in our studies. The acoustic properties of speech samples produced by children in the context of a nonword repetition task were measured. We used a Monte Carlo cross-validation with an ROC (Receiving Operator Characteristic) supervised k-Means clustering algorithm to develop a classification model that can differentially classify a child with an unknown disorder. We showed that voice acoustics classified autism diagnosis with an overall accuracy of 91% [CI95%, 90.40%-91.65%] against TD children, and of 85% [CI95%, 84.5%-86.6%] against an heterogenous group of non-autistic children. Accuracy reported here with multivariate analysis combined with Monte Carlo cross-validation is higher than in previous studies. Our findings demonstrate that easy-to-measure voice acoustic parameters could be used as a diagnostic aid tool, specific to ASD.

Metamorphic proteins at the basis of human autophagy initiation and lipid transfer.

Autophagy is a conserved intracellular degradation pathway that generates de novo double-membrane autophagosomes to target a wide range of material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly of a contact site between the ER and the nascent autophagosome. Here, we report the in vitro reconstitution of a full-length seven-subunit human autophagy initiation supercomplex built on a core complex of ATG13-101 and ATG9. Assembly of this core complex requires the rare ability of ATG13 and ATG101 to switch between distinct folds. The slow spontaneous metamorphic conversion is rate limiting for the self-assembly of the supercomplex. The interaction of the core complex with ATG2-WIPI4 enhances tethering of membrane vesicles and accelerates lipid transfer of ATG2 by both ATG9 and ATG13-101. Our work uncovers the molecular basis of the contact site and its assembly mechanisms imposed by the metamorphosis of ATG13-101 to regulate autophagosome biogenesis in space and time.

Does Phonological Complexity Provide a Good Index of Language Disorder in Children With Cochlear Implants?

Purpose Phonological complexity is known to be a good index of developmental language disorder (DLD) in normal-hearing children, who have major difficulties on some complex structures. Some deaf children with cochlear implants (CIs) present a profile that evokes DLD, with persistent linguistic difficulties despite good audiological and environmental conditions. However, teasing apart what is related to auditory deficit or to language disorder remains complex. Method We compared the performance of three groups of school-age children, 33 children with CI, 22 with DLD, and 24 with typical development, on a nonword repetition (NWR) task based on phonological complexity. Children with CI were studied regarding their linguistic profile, categorized in four subgroups ranging from excellent to very poor performance. Influence of syllable length and phonological structures on the results of all the children were explored. Results The NWR task correctly distinguished children with DLD from typically developing children, and also children with CI with the poorest linguistic performance from other children with CI. However, most complex phonological structures did not reliably identify children with CI displaying a profile similar to that of children with DLD because these structures were difficult for all of the children with CI. The simplest phonological structures were better at detecting persistent language difficulties in children with CI, as they were challenging only for the children with the poorest language outcomes. Conclusions The most complex phonological structures are not good indices of language disorder in children with CI. Phonological complexity represents a gradient of difficulty that affects normal-hearing and deaf children differently.

Conserved GxxxG and WN motifs of MIC13 are essential for bridging two MICOS subcomplexes.

Mitochondrial ultrastructure is highly adaptable and undergoes dynamic changes upon physiological and energetic cues. MICOS (mitochondrial contact site and cristae organizing system), a large oligomeric protein complex, maintains mitochondrial ultrastructure as it is required for formation of crista junctions (CJs) and contact sites. MIC13 acts as a critical bridge between two MICOS subcomplexes. Deletion of MIC13 causes loss of CJs resulting in cristae accumulating as concentric rings and specific destabilization of the MIC10-subcomplex. Mutations in MIC13 are associated with infantile lethal mitochondrial hepato-encephalopathy, yet functional regions within MIC13 were not known. To identify and characterize such regions, we systemically generated 20 amino-acids deletion variants across the length of MIC13. While deletion of many of these regions of MIC13 is dispensable for its stability, the N-terminal region and a stretch between amino acid residues 84 and 103 are necessary for the stability and functionality of MIC13. We could further locate conserved motifs within these regions and found that a GxxxG motif in the N-terminal transmembrane segment and an internal WN motif are essential for stability of MIC13, formation of the MIC10-subcomplex, interaction with MIC10- and MIC60-subcomplexes and maintenance of cristae morphology. The GxxxG motif is required for membrane insertion of MIC13. Overall, we systematically found important conserved residues of MIC13 that are required to perform the bridging between the two MICOS subcomplexes. The study improves our understanding of the basic molecular function of MIC13 and has implications for its role in the pathogenesis of a severe mitochondrial disease.

Locoregional relapses in the ACCORD 12/0405-PRODIGE 02 study: Dosimetric study and risk factors.

PURPOSE: The aim of this study is to correlate locoregional relapse with radiation therapy volumes in patients with rectal cancer treated with neoadjuvant chemoradiation in the ACCORD 12/0405-PRODIGE 02 trial. PATIENTS AND METHODS: We identified patients who had a locoregional relapse included in ACCORD 12's database. We studied their clinical, radiological, and dosimetric data to analyze the dose received by the area of relapse. RESULTS: 39 patients (6.5%) presented 54 locoregional relapses. Most of the relapses were in-field (n = 21, 39%) or marginal (n = 13, 24%) with only six out-of-field (11%), 14 could not be evaluated. Most of them happened in the anastomosis, the perirectal space, and the usual lymphatic drainage areas (presacral and posterior lateral lymph nodes). Only patients treated for a lower rectum adenocarcinoma had a relapse outside of the treated volume. 2 patients with T4 tumors extending into anterior pelvic organs had relapses in anterior lateral and external iliac lymph nodes. CONCLUSIONS: Lowering the upper limit of the treatment field for low rectal tumors increased the risk of out of the field recurrence. For very low tumors, including the inguinal lymph nodes in the treated volume should be considered. Recording locoregional involvement, treated volumes, and relapse areas in future prospective trials would be of paramount interest to refine delineation guidelines.

Brain responses to change in phonological structures of varying complexity in children and adults.

Language-related change-detection processes are often investigated using syllables that are very simple in terms of phonological structure. However, phonological complexity is known to be challenging for young typically developing children and pathological populations. We investigated brain correlates of phonological processing and their age-related changes with a passive change-detection protocol including stimuli of varying phonological complexity, which allowed comparing responses to simple and complex phonological deviancies. Mismatch Negativity (MMN) and Late Discriminative Negativity (LDN) responses were recorded in both school-age children (n = 22) and adults (n = 24). MMN was similar for simple and complex phonological deviancy in both groups, whereas LDN appeared to be modulated by phonological complexity, albeit with different patterns according to age. In response to complex phonological change, children displayed a larger LDN response with a typical fronto-central scalp distribution, while adults showed an additional right-posterior activity but no larger amplitude than for simple change. Thus, LDN appears to be a good electrophysiological index of phonological complexity processing. This study validated the use of the LDN through this protocol for the investigation of phonological complexity processing throughout the development.

TiO2 Anatase Solutions for Electron Transporting Layers in Organic Photovoltaic Cells.

Reflux of a solution of [Ti8 O12 (H2 O)24 ]Cl8 ⋅HCl⋅7 H2 O as titanium precursor at 120 °C for 24 h leads to a transparent colloidal solution of nanosized crystallized anatase TiO2 . The adjustment of the particle size and composition of the dispersant is monitored through the initial water content while controlling the conversion of propylene carbonate into propylene glycol during reflux. The solutions were processed as thin films to produce electron transporting layers in hybrid bulk heterojunction solar cells, by using a blend of P3HT:PCBM polymers as absorbers, in inverted architectures. The solutions obtained by reflux were demonstrated to produce suitable electron transporting layers.