The role of EGFR double minutes in modulating the response of malignant gliomas to radiotherapy.

EGFR amplification in cells having double minute chromosomes (DM) is commonly found in glioblastoma multiforme (GBM); however, how much it contributes to the current failure to treat GBM successfully is unknown. We studied two syngeneic primary cultures derived from a GBM with and without cells carrying DM, for their differential molecular and metabolic profiles, in vivo growth patterns, and responses to irradiation (IR). Each cell line has a distinct molecular profile consistent with an invasive "go" (with DM) or angiogenic "grow" phenotype (without DM) demonstrated in vitro and in intracranial xenograft models. Cells with DM were relatively radio-resistant and used higher glycolytic respiration and lower oxidative phosphorylation in comparison to cells without them. The DM-containing cell was able to restore tumor heterogeneity by mis-segregation of the DM-chromosomes, giving rise to cell subpopulations without them. As a response to IR, DM-containing cells switched their respiration from glycolic metabolism to oxidative phosphorylation and shifted molecular profiles towards that of cells without DM. Irradiated cells with DM showed the capacity to alter their extracellular microenvironment to not only promote invasiveness of the surrounding cells, regardless of DM status, but also to create a pro-angiogenic tumor microenvironment. IR of cells without DM was found primarily to increase extracellular MMP2 activity. Overall, our data suggest that the DM-containing cells of GBM are responsible for tumor recurrence due to their high invasiveness and radio-resistance and the mis-segregation of their DM chromosomes, to give rise to fast-growing cells lacking DM chromosomes

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Sortase-Mediated Surface Functionalization of Stimuli-Responsive Microgels

In this work we explored an enzyme-mediated method for selective and efficient decoration of aqueous microgels with biomolecules. Poly­(<i>N</i>-vinylcaprolactam) (VCL) microgels with varied amounts of glycidyl methacrylate (GMA) as comonomer incorporated in the microgel shell were synthesized and characterized in regard to their size, swelling degree, and temperature-responsiveness in aqueous solutions. The surface of the PVCL/GMA microgel containing 5 mol % glycidyl methyacrylate was modified by grafting of a specific recognition peptide sequence (LPETG) for Sortase A from Staphylococcus aureus (Sa-SrtA_Δ59). Sortase-mediated conjugation of the enhanced Green Fluorescent Protein (eGFP) carrying a N-terminal triglycine tag to LPETG-modified microgels was successfully performed. Conjugation of eGFP to the microgel surface was qualitatively proven by confocal microscopy and by fluorescence intensity measurements. The developed protocol enables a precise control of the amount of eGFP grafted to the microgel surface as evidenced by the linear increase of fluorescence intensity of modified microgel samples. The kinetic of the sortase-mediated coupling reaction was determined by time-dependent fluorescence intensity measurements. In summary, sortase-mediated coupling reactions are a simple and powerful technique for targeted surface functionalization of stimuli-responsive microgels with biomolecules

Reversible O–H bond activation by tripodal tris(nitroxide) aluminum and gallium complexes

Herein we report the preparation and characterization of the Group 13 metal complexes of a tripodal tris(nitroxide) based ligand, designated (TriNOx3−)M (M = Al (1), Ga (2), In (3)). Complexes 1 and 2 both activate the O–H bond of a range of alcohols spanning a ~13 pKa unit range via an element-ligand cooperative pathway to afford the zwitterionic complexes (HTriNOx2–)M–OR. Structures of these alcohol adduct products are discussed. We demonstrate that the thermodynamic and kinetic aspects of the reactions are both influenced by the identity of the metal, with 1 having higher reaction equilibrium constants and proceeding at a faster rate relative to 2 for any given alcohol. These parameters are also influenced by the pKa of the alcohol, with more acidic alcohols reacting both to more completion and faster than their less acidic counterparts. Possible mechanistic pathways are discussed

Reversible O–H Bond Activation by Tripodal tris(Nitroxide) Aluminum and Gallium Complexes

Herein, we report the preparation and characterization of the Group 13 metal complexes of a tripodal tris(nitroxide)-based ligand, designated (TriNOx3–)M (M = Al (1), Ga (2), In (3)). Complexes 1 and 2 both activate the O–H bond of a range of alcohols spanning a ∼10 pKa unit range via an element-ligand cooperative pathway to afford the zwitterionic complexes (HTriNOx2–)M–OR. Structures of these alcohol adduct products are discussed. We demonstrate that the thermodynamic and kinetic aspects of the reactions are both influenced by the identity of the metal, with 1 having higher reaction equilibrium constants and proceeding at a faster rate relative to 2 for any given alcohol. These parameters are also influenced by the pKa of the alcohol, with more acidic alcohols reacting both to more completion and faster than their less acidic counterparts. Possible mechanistic pathways for the O–H activation are discussed

Coordination Chemistry of a Strongly-Donating Hydroxylamine with Early Actinides: An Investigation of Redox Properties and Electronic Structure

Separations of f-block elements are a critical aspect of nuclear waste processing. Redox-based separations offer promise, but challenges remain in stabilizing and differentiating actinides in high oxidation states. The investigation of new ligand types that provide thermodynamic stabilization to high-valent actinides is essential for expanding their fundamental chemistry and to elaborate new separation techniques and storage methods. We report herein the preparation and characterization of Th and U complexes of the pyridyl-hydroxylamine ligand, <i>N</i>-<i>tert</i>-butyl-<i>N</i>-(pyridin-2-yl)­hydroxylamine (pyNO^–). Electrochemical studies performed on the homoleptic complexes [M­(pyNO)₄] (M = Th, U) revealed significant stabilization of the U complex upon one-electron oxidation. The salt [U­(pyNO)₄]⁺ was isolated by chemical oxidation of [U­(pyNO)₄]; spectroscopic and computational data support assignment as a U^V cation

The role of EGFR double minutes in modulating the response of malignant gliomas to radiotherapy.

EGFR amplification in cells having double minute chromosomes (DM) is commonly found in glioblastoma multiforme (GBM); however, how much it contributes to the current failure to treat GBM successfully is unknown. We studied two syngeneic primary cultures derived from a GBM with and without cells carrying DM, for their differential molecular and metabolic profiles, in vivo growth patterns, and responses to irradiation (IR). Each cell line has a distinct molecular profile consistent with an invasive "go" (with DM) or angiogenic "grow" phenotype (without DM) demonstrated in vitro and in intracranial xenograft models. Cells with DM were relatively radio-resistant and used higher glycolytic respiration and lower oxidative phosphorylation in comparison to cells without them. The DM-containing cell was able to restore tumor heterogeneity by mis-segregation of the DM-chromosomes, giving rise to cell subpopulations without them. As a response to IR, DM-containing cells switched their respiration from glycolic metabolism to oxidative phosphorylation and shifted molecular profiles towards that of cells without DM. Irradiated cells with DM showed the capacity to alter their extracellular microenvironment to not only promote invasiveness of the surrounding cells, regardless of DM status, but also to create a pro-angiogenic tumor microenvironment. IR of cells without DM was found primarily to increase extracellular MMP2 activity. Overall, our data suggest that the DM-containing cells of GBM are responsible for tumor recurrence due to their high invasiveness and radio-resistance and the mis-segregation of their DM chromosomes, to give rise to fast-growing cells lacking DM chromosomes