Le 16e siècle romain correspond au déploiement au long cours de sa connaissance et redéfinition de l’Orient, à la croisée de multiples savoirs et pratiques, savantes ou ordinaires, qui redessinent ...les liens entre Antiquité et monde contemporain. L’article en propose une lecture qui vise à mettre en lumière une réarticulation des références spatio-temporelles de l’Urbs, espace privilégié d’une confrontation de l’Egypte, construite en pivot de l’Orient ancien, et du Japon, expression du moderne Orient extrême. Il fait l’hypothèse que cette confrontation ouvre des voies de compréhension nouvelles aux processus de production des savoirs dans la capitale pontificale.
KRAS is the undisputed champion of oncogenes, and despite its prominent role in oncogenesis as mutated gene, KRAS mutation appears infrequent in gliomas. Nevertheless, gliomas are considered ...KRAS-driven cancers due to its essential role in mouse malignant gliomagenesis. Glioblastoma is the most lethal primary brain tumor, often associated with disturbed RAS signaling. For newly diagnosed GBM, the current standard therapy is alkylating agent chemotherapy combined with radiotherapy. Cisplatin is one of the most effective anticancer drugs and is used as a first-line treatment for a wide spectrum of solid tumors (including medulloblastoma and neuroblastoma) and many studies are currently focused on new delivery modalities of effective cisplatin in glioblastoma. Its mechanism of action is mainly based on DNA damage, inducing the formation of DNA adducts, triggering a series of signal-transduction pathways, leading to cell-cycle arrest, DNA repair and apoptosis.
Long-term cultures of human glioblastoma, U87MG and U251MG, were either treated with cis-diamminedichloroplatinum (cisplatin, CDDP) and/or MEK-inhibitor PD98059. Cytotoxic responses were assessed by cell viability (MTT), protein expression (Western Blot), cell cycle (PI staining) and apoptosis (TUNEL) assays. Further, gain-of-function experiments were performed with cells over-expressing mutated hypervariable region (HVR) KRAS
plasmids.
Here, we studied platinum-based chemosensitivity of long-term cultures of human glioblastoma from the perspective of KRAS expression, by using CDDP and MEK-inhibitor. Endogenous high KRAS expression was assessed at transcriptional (qPCR) and translational levels (WB) in a panel of primary and long-term glioblastoma cultures. Firstly, we measured immediate cellular adjustment through direct regulation of protein concentration of K-Ras4B in response to cisplatin treatment. We found increased endogenous protein abundance and involvement of the effector pathway RAF/MEK/ERK mitogen-activated protein kinase (MAPK) cascade. Moreover, as many MEK inhibitors are currently being clinically evaluated for the treatment of high-grade glioma, so we concomitantly tested the effect of the potent and selective non-ATP-competitive MEK1/2 inhibitor (PD98059) on cisplatin-induced chemosensitivity in these cells. Cell-cycle phase distribution was examined using flow cytometry showing a significant cell-cycle arrest in both cultures at different percentage, which is modulated by MEK inhibition. Cisplatin-induced cytotoxicity increased sub-G1 percentage and modulates G2/M checkpoint regulators cyclins D1 and A. Moreover, ectopic expression of a constitutively active KRAS
rescued CDDP-induced apoptosis and different HVR point mutations (particularly Ala 185) reverted this phenotype.
These findings warrant further studies of clinical applications of MEK1/2 inhibitors and KRAS as 'actionable target' of cisplatin-based chemotherapy for glioblastoma.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Brain differentiation is maximized in a very limited number of very fast, intermittent events.•Transition matrices based on avalanches are effective in selecting the locations and moments where ...higher-order perturbations spread.•Non-linear part of the brain signals carries most of the subject-specific information.
Subject differentiation bears the possibility to individualize brain analyses. However, the nature of the processes generating subject-specific features remains unknown. Most of the current literature uses techniques that assume stationarity (e.g., Pearson's correlation), which might fail to capture the non-linear nature of brain activity. We hypothesize that non-linear perturbations (defined as neuronal avalanches in the context of critical dynamics) spread across the brain and carry subject-specific information, contributing the most to differentiability. To test this hypothesis, we compute the avalanche transition matrix (ATM) from source-reconstructed magnetoencephalographic data, as to characterize subject-specific fast dynamics. We perform differentiability analysis based on the ATMs, and compare the performance to that obtained using Pearson's correlation (which assumes stationarity). We demonstrate that selecting the moments and places where neuronal avalanches spread improves differentiation (P < 0.0001, permutation testing), despite the fact that most of the data (i.e., the linear part) are discarded. Our results show that the non-linear part of the brain signals carries most of the subject-specific information, thereby clarifying the nature of the processes that underlie individual differentiation. Borrowing from statistical mechanics, we provide a principled way to link emergent large-scale personalized activations to non-observable, microscopic processes.
Three-dimensional motion analysis represents a quantitative approach to assess spatio-temporal and kinematic changes in health and disease. However, these parameters provide only segmental ...information, discarding minor changes of complex whole body kinematics characterizing physiological and/or pathological conditions. We aimed to assess how levodopa intake affects the whole body, analyzing the kinematic interactions during gait in Parkinson's disease (PD) through network theory which assess the relationships between elements of a system. To this end, we analysed gait data of 23 people with PD applying network theory to the acceleration kinematic data of 21 markers placed on participants' body landmarks. We obtained a matrix of kinematic interactions (i.e., the kinectome) for each participant, before and after the levodopa intake, we performed a topological analysis to evaluate the large-scale interactions among body elements, and a multilinear regression analysis to verify whether the kinectome's topology could predict the clinical variations induced by levodopa. We found that, following levodopa intake, patients with PD showed less trunk and head synchronization (p-head = 0.048; p-7th cervical vertebrae = 0.032; p-10th thoracic vertebrae = 0.006) and an improved upper-lower limbs synchronization (elbows right, p = 0.002; left, p = 0.005), (wrists right, p = 0.003; left, p = 0.002; knees right, p = 0.003; left, p = 0.039) proportional to the UPDRS-III scores. These results may be attributable to the reduction of rigidity, following pharmacological treatment.
Gendered Touch Antonelli, Francesca; Romano, Antonella; Savoia, Paolo
2022, Letnik:
9
eBook, Book
The history of science, the history of women, and gender history - Gendered Touch offers new perspectives on the intersections between the textual and the embodied nature of scientific knowledge in ...early modern Europe.
The estrogen receptor (ER) signaling regulates numerous physiological processes mainly through activation of gene transcription (genomic pathways). Caveolin1 (CAV1) is a membrane-resident protein ...that behaves as platform to enable different signaling molecules and receptors for membrane-initiated pathways. CAV1 directly interacts with ERs and allows their localization on membrane with consequent activation of ER-non-genomic pathways. Loss of CAV1 function is a common feature of different types of cancers, including breast cancer. Two protein isoforms, CAV1α and CAV1β, derived from two alternative translation initiation sites, are commonly described for this gene. However, the exact transcriptional regulation underlying CAV1 expression pattern is poorly elucidated. In this study, we dissect the molecular mechanism involved in selective expression of CAV1β isoform, induced by estrogens and downregulated in breast cancer. Luciferase assays and Chromatin immunoprecipitation demonstrate that transcriptional activation is triggered by estrogen-responsive elements embedded in CAV1 intragenic regions and DNA-binding of estrogen-ER complexes. This regulatory control is dynamically established by local chromatin changes, as proved by the occurrence of histone H3 methylation/demethylation events and association of modifier proteins as well as modification of H3 acetylation status. Thus, we demonstrate for the first time, an estrogen-ERs-dependent regulatory circuit sustaining selective CAV1β expression.
Les années quatre-vingt-dix ont constitué, du point de vue de l’histoire des sciences, un important moment de mutation du paysage historiographique français. On pourrait même dire que l’année ...inaugurale en fut 1993. C’est à cette date que les études sur les sciences ont commencé à recomposer le paysage intellectuel et institutionnel comme en témoigne notamment la réception controversée d’un livre de la décennie précédente mais dont les jeux de la traduction retardaient la discussion : Léviat...
Investigating mobility or circulation within the framework of the history of science is somehow new, and is deeply rooted in the in-depth changes that took place in this field. The issue of agency, ...the questions related to actors, their practices and the systems of communications they shape and negotiate in order to produce science, in other words, the analysis of knowledge as a process, are the preliminary conditions for questioning movements, spaces and places as part of the construction of knowledge itself. Before the rise of this new historiographical trend, sciences were mostly studied as universal, as expressed by the development of modern science. The paper explores the multiple paths which led to the current collective research agenda: what is at stake thus is an invitation, beyond history of science and knowledge, to rethink the relation both between Europe and the world in the early modern period, and between the different social sciences today.
Histone methylation changes and formation of chromatin loops involving enhancers, promoters and 3' end regions of genes have been variously associated with active transcription in eukaryotes. We have ...studied the effect of activation of the retinoic A receptor, at the RARE-promoter chromatin of CASP9 and CYP26A1 genes, 15 and 45 min following RA exposure, and we found that histone H3 lysines 4 and 9 are demethylated by the lysine-specific demethylase, LSD1 and by the JMJ-domain containing demethylase, D2A. The action of the oxidase (LSD1) and a dioxygenase (JMJD2A) in the presence of Fe++ elicits an oxidation wave that locally modifies the DNA and recruits the enzymes involved in base and nucleotide excision repair (BER and NER). These events are essential for the formation of chromatin loop(s) that juxtapose the RARE element with the 5' transcription start site and the 3' end of the genes. The RARE bound-receptor governs the 5' and 3' end selection and directs the productive transcription cycle of RNA polymerase. These data mechanistically link chromatin loops, histone methylation changes and localized DNA repair with transcription.
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•The Clinical Connectome Fingerprint (CCF) is an approach able to determine subject-specific connectivity features in a given population.•Patients with Amyotrophic lateral sclerosis ...(ALS) show reduced identifiability compared to healthy controls.•The I-clinical is a measure of subject-specific clinical identification and predict both the motor impairment and the disease progression in ALS patients.•The predictive power of the clinical fingerprint may represent a promising tool in ALS clinical management.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by functional connectivity alterations in both motor and extra-motor brain regions. Within the framework of network analysis, fingerprinting represents a reliable approach to assess subject-specific connectivity features within a given population (healthy or diseased). Here, we applied the Clinical Connectome Fingerprint (CCF) analysis to source-reconstructed magnetoencephalography (MEG) signals in a cohort of seventy-eight subjects: thirty-nine ALS patients and thirty-nine healthy controls. We set out to develop an identifiability matrix to assess the extent to which each patient was recognisable based on his/her connectome, as compared to healthy controls. The analysis was performed in the five canonical frequency bands. Then, we built a multilinear regression model to test the ability of the “clinical fingerprint” to predict the clinical evolution of the disease, as assessed by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-r), the King’s disease staging system, and the Milano-Torino Staging (MiToS) disease staging system. We found a drop in the identifiability of patients in the alpha band compared to the healthy controls. Furthermore, the “clinical fingerprint” was predictive of the ALSFRS-r (p = 0.0397; β = 32.8), the King’s (p = 0.0001; β = −7.40), and the MiToS (p = 0.0025; β = −4.9) scores. Accordingly, it negatively correlated with the King’s (Spearman’s rho = -0.6041, p = 0.0003) and MiToS scales (Spearman’s rho = −0.4953, p = 0.0040). Our results demonstrated the ability of the CCF approach to predict the individual motor impairment in patients affected by ALS. Given the subject-specificity of our approach, we hope to further exploit it to improve disease management.
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