Подходы к оценке инновационной восприимчивости организации

Материалы XX Междунар. науч.-техн. конф. студентов, аспирантов и молодых ученых, Гомель, 23–24 апр. 2020 г

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Organization and regulation of mitochondrial gene expression

Mitochondria possess their own genome, remnant of the ancestral eubacterial endosymbiont DNA. This mitochondrial genome encodes mostly few key subunits of the respiratory chain. In order to synthesize these few proteins, mitochondria contain a complete gene expression machinery. Crucially, during the evolution, this apparatus dramatically diverged from its bacterial original counterpart, acquiring unique organellar characteristics. Hence, the mechanisms underlying organization and regulation of mitochondrial gene expression are still enigmatic. In this thesis, I used the model organism Saccharomyces cerevisiae to reveal few aspects of mitochondrial gene expression. Surprisingly, I report that translation initiation strongly diverged from the bacterial one. In fact, the mitochondrial counterpart of the bacterial translation initiation factor 3 is dispensable in yeast. Furthermore, the research made in this work contributed to establish the proximity labelling technique BioID for yeast mitochondrial proteins. This method permitted to analyse extensively the mitochondrial gene expression milieu, creating a comprehensive proximity-based network of factors involved in biogenesis of mitochondrial synthesized proteins. This protein network revealed a unique organization of factors involved in mitochondrial gene expression, meticulously tailored for the synthesis of few organellar proteins. Crucially, we could identify a clear spatial distribution of factors according to their biological function. Moreover, the thesis describes how the polypeptide tunnel exit hosts proteins involved in multiple functions. First, the results show how factors involved in early maturation of Cox1, the core subunit of complex IV of the respiratory chain, reside at the polypeptide tunnel exit. Second, we demonstrate that the synthesis of cytochrome b, subunit of complex III, is also activated at the polypeptide tunnel exit. In fact, proteins taking part in the regulation of mitochondrial gene expression called translational activators interact with this area in an alternate fashion. When synthesis of cytochrome b is repressed, its coding mRNA COB is sequestered at the polypeptide tunnel exit via the binding to Cbs1, a translational activator. The signal that triggers translation initiation is given by Cbp3-Cbp6, a complex that participates in cytochrome b assembly. When a previously synthesized cytochrome b is correctly assembled into complex III, Cbp3-Cbp6 interacts with the polypeptide tunnel exit, forcing the relocation of Cbs1, and making COB mRNA available for a new round of translation. This mechanism represents a unique form of tuning between mitochondrial and nuclear gene expression systems, essential for the correct assembly of complexes made up by proteins of dual origin. In summary, the work presented in this thesis reveals novel features of the organization and regulation of the mitochondrial gene expression, highlighting many distinctive organellar features. The concepts and techniques presented here will be a starting point to elucidate many unknown aspects of mitochondrial protein synthesis.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Submitted.</p

Molecular Connectivity of Mitochondrial Gene Expression and OXPHOS Biogenesis

Mitochondria contain their own gene expression systems, including membrane-bound ribosomes dedicated to synthesizing a few hydrophobic subunits of the oxidative phosphorylation (OXPHOS) complexes. We used a proximity-dependent biotinylation technique, BioID, coupled with mass spectrometry to delineate in baker’s yeast a comprehensive network of factors involved in biogenesis of mitochondrial encoded proteins. This mitochondrial gene expression network (MiGENet) encompasses proteins involved in transcription, RNA processing, translation, or protein biogenesis. Our analyses indicate the spatial organization of these processes, thereby revealing basic mechanistic principles and the proteins populating strategically important sites. For example, newly synthesized proteins are directly handed over to ribosomal tunnel exit-bound factors that mediate membrane insertion, co-factor acquisition, or their mounting into OXPHOS complexes in a special early assembly hub. Collectively, the data reveal the connectivity of mitochondrial gene expression, reflecting a unique tailoring of the mitochondrial gene expression system

Aim-less translation : loss of Saccharomyces cerevisiae mitochondrial translation initiation factor mIF3/Aim23 leads to unbalanced protein synthesis

The mitochondrial genome almost exclusively encodes a handful of transmembrane constituents of the oxidative phosphorylation (OXPHOS) system. Coordinated expression of these genes ensures the correct stoichiometry of the system's components. Translation initiation in mitochondria is assisted by two general initiation factors mIF2 and mIF3, orthologues of which in bacteria are indispensible for protein synthesis and viability. mIF3 was thought to be absent in Saccharomyces cerevisiae until we recently identified mitochondrial protein Aim23 as the missing orthologue. Here we show that, surprisingly, loss of mIF3/Aim23 in S. cerevisiae does not indiscriminately abrogate mitochondrial translation but rather causes an imbalance in protein production: the rate of synthesis of the Atp9 subunit of F1F0 ATP synthase (complex V) is increased, while expression of Cox1, Cox2 and Cox3 subunits of cytochrome c oxidase (complex IV) is repressed. Our results provide one more example of deviation of mitochondrial translation from its bacterial origins

The tooth of a giant sea creature Otodus (Megaselachus) in the material culture of Neolithic maritime hunter-gatherers at Sharbithat (Sultanate of Oman)

International audienceA mega-tooth belonging to a Miocene fossil shark was discovered along the shores of the Arabian Sea inside one of the Neolithic domestic settlements at Sharbithat (SHA-10) (Sultanate of Oman). Attributed to a representative of the extinct genus Otodus (Megaselachus), this tooth is the first ever discovered in the Arabian Peninsula. In the field, research permitted the localization and study, a few kilometres away, of the palaeontological deposit where this retrieval was made. The shark, traditionally extensively hunted on the shores of the Arabian Sea, is well attested in the region's Neolithic ichthyological assemblages. Moreover, during this period, some groups of seaborne hunters were specialized in this form of fishing, which was indeed quite dangerous. But why did an individual some 5,500 years ago collect this curio, an unusual fossil, but also one he could easily recognize? The fossils of large sharks sometimes played an important part in ancient societies. Could this also have been the case in SouthEastern Arabia