Search

ABSTRACTKRAS genes belong to the most frequently mutated family of oncogenes in cancer. The G12C mutation, found in a third of lung, half of colorectal and pancreatic cancer cases, is believed to be responsible for a substantial number of cancer deaths. For 30 years, KRAS has been the subject of extensive drug-targeting efforts aimed at targeting KRAS protein itself, but also its post-translational modifications, membrane localization, protein–protein interactions and downstream signalling pathways. So far, most KRAS targeting strategies have failed, and there are no KRAS-specific drugs available. However, clinical candidates targeting the KRAS G12C protein have recently been developed. MRTX849 and recently approved Sotorasib are covalent binders targeting the mutated cysteine 12, occupying Switch II pocket.Herein, we describe two fragment screening drug discovery campaigns that led to the identification of binding pockets on the KRAS G12C surface that have not previously been described. One screen focused on non-covalent binders to KRAS G12C, the other on covalent binders.

MRI abnormalities included cerebrovascular lesions, perfusion abnormalities, cytotoxic lesions of the corpus callosum, intensive care unit–related complications, white matter–enhancing lesions, and basal ganglia abnormalities.

The sense of agency refers to the conscious experience of authorship and control over actions.

18-Vinylprogesterone (18-VP) and 18-ethynylprogesterone (18-EP) have proved to be potent suicide inhibitors of P-45011β, the last enzyme of aldosterone biosynthesis (Delorme, C.; Piffeteau, A.; Viger, A.; Marquet, A. Eur. J. Biochem.1995, 232, 247; Delorme, C.; Piffeteau, A.; Sobrio, F.; Marquet, A. Eur. J. Biochem.1997, 248, 252). This paper describes the synthesis of 18-vinyldeoxycorticosterone (18-VDOC), an analogue of deoxycorticosterone (DOC), the physiological substrate of the enzyme, and the evaluation of its reversible inhibiting properties for deoxycorticosterone and corticosterone oxidation by the bovine enzyme. 18-VDOC has been obtained by hydroxylation at C-21 of a 18-VP precursor. Its reversible Kivalues are, respectively, 0.3μM for the 11β-hydroxylation and 0.8μM for the 18-hydroxylation. Hence, 18-VDOC is the strongest competitive inhibitor of bovine P-45011βdescribed so far, but in contrast with 18-VP, it does not inhibit more efficiently the 18-hydroxylation than the 11-hydroxylation.

Paracoccus denitrificans is a facultative anaerobic bacterium that has the capacity to adjust its metabolic infrastructure, quantitatively and/or qualitatively, to the prevailing growth condition. In this bacterium the relative activity of distinct catabolic pathways is subject to a hierarchical control. In the presence of oxygen the aerobic respiration, the most efficient way of electron transfer-linked phosphorylation, has priority. At high oxygen tensionsP. denitrificans synthesizes an oxidase with a relatively low affinity for oxygen, whereas under oxygen limitation a high-affinity oxidase appears specifically induced. During anaerobiosis, the pathways with lower free energy-transducing efficiency are induced. In the presence of nitrate, the expression of a number of dehydrogenases ensures the continuation of oxidative phosphorylation via denitrification. After identification of the structural components that are involved in both the aerobic and the anaerobic respiratory networks ofP. denitrificans, the intriguing next challenge is to get insight in its regulation. Two transcription regulators have recently been demonstrated to be involved in the expression of a number of aerobic and/or anaerobic respiratory complexes inP. denitrificans. Understanding of the regulation machinery is beginning to emerge and promises much excitement in discovery.

IMPORTANCE: There is evidence of central nervous system impairments associated with coronavirus disease 2019 (COVID-19) infection, including encephalopathy. Multimodal monitoring of patients with COVID-19 may delineate the specific features of COVID-19–related encephalopathy and guide clinical management. OBJECTIVES: To investigate clinical, biological, and brain magnetic resonance imaging (MRI) findings in association with electroencephalographic (EEG) features for patients with COVID-19, and to better refine the features of COVID-19–related encephalopathy. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study conducted in Pitié-Salpêtrière Hospital, Paris, France, enrolled 78 hospitalized adults who received a diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and underwent EEG between March 30 and June 11, 2020. EXPOSURES: Detection of SARS-CoV-2 from a nasopharyngeal specimen using a reverse transcription–polymerase chain reaction assay or, in the case of associated pneumonia, on a computed tomography scan of the chest. MAIN OUTCOMES AND MEASURES: Data on the clinical and paraclinical features of the 78 patients with COVID-19 were retrieved from electronic patient records. RESULTS: Of 644 patients who were hospitalized for COVID-19, 78 (57 men [73%]; mean [SD] age, 61 [12] years) underwent EEG. The main indications for EEG were delirium, seizure-like events, and delayed awakening in the intensive care unit after stopping treatment with sedatives. Sixty-nine patients showed pathologic EEG findings, including metabolic-toxic encephalopathy features, frontal abnormalities, periodic discharges, and epileptic activities. Of 57 patients who underwent brain MRI, 41 showed abnormalities, including perfusion abnormalities, acute ischemic lesions, multiple microhemorrhages, and white matter–enhancing lesions. Fifty-five patients showed biological abnormalities, including dysnatremia, kidney failure, and liver dysfunction, the same day as the EEG. The results of cerebrospinal fluid analysis were negative for SARS-Cov-2 for all tested patients. Nine patients who had no identifiable cause of brain injury outside COVID-19 were further isolated; their brain injury was defined as COVID-19–related encephalopathy. They represented 1% (9 of 644) of patients with COVID-19 requiring hospitalization. Six of these 9 patients had movement disorders, 7 had frontal syndrome, 4 had brainstem impairment, 4 had periodic EEG discharges, and 3 had MRI white matter–enhancing lesions. CONCLUSIONS AND RELEVANCE: The results from this cohort of patients hospitalized with COVID-19 suggest there are clinical, EEG, and MRI patterns that could delineate specific COVID-19–related encephalopathy and guide treatment strategy.

Récemment, la présence d’anticorps anti-myelin oligodendrocyte glycoprotein(MOG) a été rapportée chez des patients présentant une névrite optique inflammatoire.

La stimulation cérébrale profonde (SCP) ciblant le globus pallidus internus (GPi) pourrait réduire l’intensité des mouvements anormaux dans la maladie de Huntington (MH), mais les données actuelles sont limitées.