Electronic structure of carbon suboxide, C3O2, has been recently described as OC→C←CO having two lone pairs at the central carbon atom, thereby called as \"Carbones\". Although it has a linear geometry, the presence of two lone pairs comes to fore when its reactivity is analyzed with two protons. However, no attention had been paid on its alternating reactivity with hydride ions. Herein, detailed quantum chemical calculations predict that carbon suboxide can also have significant hydride ion affinity. This reactivity is in tune with σ0π2 carbene character of carbon suboxide. This study also shows that such a σ0π2 carbene character is also prevalent in carbodiphosphorane, C(PH3)2. This bonding situation has been hitherto unexplored in \"Carbone\" chemistry.

BACKGROUND: In this article, we adapt a recent proposition to use a Fermi-Dirac-type population scheme on Kohn-Sham molecular orbitals to the case of an interaction with a thermalised electrode. This allows to derive a fundamental non-linear equation linking the chemical potential of the electrode and the amount of charge transferred to the system under study, hence allows to quantify the propensity to charge transfer (philicity). This methodology is applied to a large set of common electrophiles and nucleophiles, showing decent relation with more standard philicity descriptors. Chemical hardness is also revisited by this approach.
METHODS: All calculations were performed using the Gaussian 16 software package at the M062X/aug-cc-pvtz level of theory. Data analysis was then performed through a Python3 dedicated program (relying on the fsolve numerical solver from the SciPy package), using Gaussian output files, and available as supplementary material.

Sulphotransferases (SULTs) are a major phase II metabolic enzyme class contributing ~20 % to the Phase II metabolism of FDA-approved drugs. Ignoring the potential for SULT-mediated metabolism leaves a strong potential for drug-drug interactions, often causing late-stage drug discovery failures or black-boxed warnings on FDA labels. The existing models use only accessibility descriptors and machine learning (ML) methods for class and site of sulfonation (SOS) predictions for SULT. In this study, a variety of accessibility, reactivity, and hybrid models and algorithms have been developed to make accurate substrate and SOS predictions. Unlike the literature models, reactivity parameters for the aliphatic or aromatic hydroxyl groups (R/Ar-O-H), the Bond Dissociation Energy (BDE) gave accurate models with a True Positive Rate (TPR)=0.84 for SOS predictions. We offer mechanistic insights to explain these novel findings that are not recognized in the literature. The accessibility parameters like the ratio of Chemgauss4 Score (CGS) and Molecular Weight (MW) CGS/MW and distance from cofactor (Dis) were essential for class predictions and showed TPR=0.72. Substrates consistently had lower BDE, Dis, and CGS/MW than non-substrates. Hybrid models also performed acceptablely for SOS predictions. Using the best models, Algorithms gave an acceptable performance in class prediction: TPR=0.62, False Positive Rate (FPR)=0.24, Balanced accuracy (BA)=0.69, and SOS prediction: TPR=0.98, FPR=0.60, and BA=0.69. A rule-based method was added to improve the predictive performance, which improved the algorithm TPR, FPR, and BA. Validation using an external dataset of drug-like compounds gave class prediction: TPR=0.67, FPR=0.00, and SOS prediction: TPR=0.80 and FPR=0.44 for the best Algorithm. Comparisons with standard ML models also show that our algorithm shows higher predictive performance for classification on external datasets. Overall, these models and algorithms (SOS predictor) give accurate substrate class and site (SOS) predictions for SULT-mediated Phase II metabolism and will be valuable to the drug discovery community in academia and industry. The SOS predictor is freely available for academic/non-profit research via the GitHub link.

Skin sensitization is a key endpoint for safety assessment, especially for cosmetics and personal care products. The adverse outcome pathway for skin sensitization and the chemical and biological events driving the induction of human skin sensitization are now well understood. Several non-animal test methods have been developed to predict sensitizer potential by measuring the impact of chemical sensitizers on these key events. In this work, we have focused on Key Event 1 (the molecular initiating step), which is based on formation of a covalent adduct between skin sensitizers and endogenous proteins and/or peptides in the skin. There exists three in-chemico assays approved by the Organization for Economic Co-operation and Development-(1) Direct Peptide Reactivity Assay (DPRA), (2) Amino Acid Derivative Reactivity Assay (ADRA), and (3) Kinetic Direct Peptide Reactivity Assay (kDPRA) to quantify peptide/amino acid derivative depletion after incubation with test chemicals. However, overestimated depletion of the cysteine-based peptide/amino acid derivatives is known in such assays because of the dimerization of the thiol group. In this present work, we report the synthesis and structural confirmation of the dimer of N-(2-[1-naphthyl]acetyl)-L-cysteine (NAC) from the ADRA assay to allow simultaneous determination of (a) peptide depletion by quantifying NAC monomer and (b) peptide dimerization by quantifying NAC dimer thereby eliminating the overestimation. We present a case study with three chemicals to demonstrate the importance of this approach. Thus, this simultaneous assay gives a more informed view of the peptide reactivity of chemicals to better identify skin sensitizers.

Reactive astrocytes are known to exert detrimental effects upon neurons in several neurodegenerative diseases, yet our understanding of how astrocytes promote neurotoxicity remains incomplete, especially in human systems. In this study, we leveraged human pluripotent stem cell (hPSC) models to examine how reactivity alters astrocyte function and mediates neurodegeneration. hPSC-derived astrocytes were induced to a reactive phenotype, at which point they exhibited a hypertrophic profile and increased complement C3 expression. Functionally, reactive astrocytes displayed decreased intracellular calcium, elevated phagocytic capacity, and decreased contribution to the blood-brain barrier. Subsequently, co-culture of reactive astrocytes with a variety of neuronal cell types promoted morphological and functional alterations. Furthermore, when reactivity was induced in astrocytes from patient-specific hPSCs (glaucoma, Alzheimer\'s disease, and amyotrophic lateral sclerosis), the reactive state exacerbated astrocytic disease-associated phenotypes. These results demonstrate how reactive astrocytes modulate neurodegeneration, significantly contributing to our understanding of a role for reactive astrocytes in neurodegenerative diseases.

Manganese complexes exhibit a rich redox chemistry, usually accompanied by structural reorganization during the redox processes often followed by ligand dissociation or association. The push-pull ligand 2,6-diguanidylpyridine (dgpy) stabilizes manganese in the oxidation states +II, +III, and + IV in the complexes [Mn(dgpy)2]n+ (n = 2-4) without change in the coordination sphere in the condensed phase [Heinze et al., Inorganic Chemistry, 2022, 61, 14616]. In the condensed phase, the manganese(IV) complex is a very strong oxidant. In the present work, we investigate the stability and redox activity of the MnIV complex and its counterion (PF6-) adducts in the gas phase, using two modified 3D Paul ion trap mass spectrometers. Six different cationic species of the type [Mnx(dgpy)2(PF6)y]n+ (x = II, III, IV, y = 0-3, n = 1-3) could be observed for the three oxidation states MnIV, MnIII, and MnII, of which one observed complex also contains a reduced dgpy ligand. MnII species showed the highest relative stability in collision induced dissociation and UV/vis photo dissociation experiments. The lowest stability is observed in the presence of one or more counterions, which correlates to a lower total charge n+. Gas phase UV/vis spectra show similar features as the condensed phase spectra only differing in relative band intensities. The strongly oxidizing MnIV complex reacts with triethylamine (NEt3) in the gas phase to give MnIII, while MnIII species show little reactivity toward NEt3.

Significant efforts have recently been exerted toward construction of singlet oxygen (1O2)-dominated catalytic oxidation systems for selective removal of organic contaminants from wastewater, with peroxides serving as the chemical source. However, the relevance of 1O2 in the removal of pollutants remains ambiguous and requires elucidation. In this study, we scrupulously exclude the significant role of 1O2 in contaminant degradation in various peroxymonosulfate (PMS) activation systems. Multiple experimental results indicate that the activation of PMS catalyzed by CuO, MnO2, Fe-doped g-C3N4 (Fe-CN), or N-doped graphite does not predominantly follow the 1O2 pathway. More importantly, the reactivity of 1O2 is remarkably overestimated in the literature, given its inferior capacity in degradation of a range of heterocyclic contaminants and aromatic compounds possessing electron-withdrawing groups. In addition, the strong physical quenching effect of water, coupled with the low oxidizing ability of 1O2, would notably reduce the utilization efficiency of peroxide, which is particularly apparent in the degradation of micropollutants. We reckon that this study is expected to end the long-running dispute associated with the relevance of 1O2 in pollutant removal.

Understanding the exohedral reactivity of metallofullerenes is crucial for its application in various fields. By systematically controlling the trapped species inside the fullerene its reactivity can be tamed. In this work we report the preferential position of 3d metal atoms inside the C36 cage and their effect on exohedral reactivity in comparison with the neutral and the dianionic cage. The Diels-Alder (DA) reaction between butadiene and all non-equivalent [5-5], [6-5] and [6-6] C-C bonds on the fullerene cage was considered for the analysis, by using density functional theory at the S12g/TZ2P level including COSMO solvation model to elucidate the complete mechanistic pathways. Our results indicate that the preferential position of the metal ion is at the position close to the upper hexagon, and that the general trend in the reactivity of bonds follows the order [5-5] > [6-5] > [6-6]. Moreover, the encapsulation of metal atoms further enhances the reactivity of these bonds, by distorting the system and delocalizing the LUMOs all over the cage.

OBJECTIVE: Assess the prognostic ability of a non-highly malignant and reactive EEG to predict good outcome after cardiac arrest (CA).
METHODS: Prospective observational multicentre substudy of the \"Targeted Hypothermia versus Targeted Normothermia after Out-of-hospital Cardiac Arrest Trial\", also known as the TTM2-trial. Presence or absence of highly malignant EEG patterns and EEG reactivity to external stimuli were prospectively assessed and reported by the trial sites. Highly malignant patterns were defined as burst-suppression or suppression with or without superimposed periodic discharges. Multimodal prognostication was performed 96 h after CA. Good outcome at 6 months was defined as a modified Rankin Scale score of 0-3.
RESULTS: 873 comatose patients at 59 sites had an EEG assessment during the hospital stay. Of these, 283 (32%) had good outcome. EEG was recorded at a median of 69 h (IQR 47-91) after CA. Absence of highly malignant EEG patterns was seen in 543 patients of whom 255 (29% of the cohort) had preserved EEG reactivity. A non-highly malignant and reactive EEG had 56% (CI 50-61) sensitivity and 83% (CI 80-86) specificity to predict good outcome. Presence of EEG reactivity contributed (p < 0.001) to the specificity of EEG to predict good outcome compared to only assessing background pattern without taking reactivity into account.
CONCLUSIONS: Nearly one-third of comatose patients resuscitated after CA had a non-highly malignant and reactive EEG that was associated with a good long-term outcome. Reactivity testing should be routinely performed since preserved EEG reactivity contributed to prognostic performance.

Laboratory stress tasks are necessary to closely investigate the stress response in a controlled environment. However, to our knowledge, no study has tested whether participating in such tasks can pose any daily life adverse effect. Fifty-three healthy participants (46 women) took part in a laboratory session where stress was induced using a typical psychosocial stressor: the repeated Montreal Imaging Stress Task (rMIST). Average levels of negative affect (NA), heart rate (HR), root mean square of successive differences (RMSSD), and skin conductance level (SCL), as well as reactivity across all these parameters as measured with the experience sampling method (ESM) in the four days prior to the laboratory session were compared with the four days following the session. We also assessed whether vulnerability to psychopathology moderated these associations. Findings showed that the task did not pose any significant adverse effect on participants. However, there was an unexpected increase in average RMSSD and a decrease in average SCL pre- to post- task. In addition, more vulnerable individuals were more likely to experience an increase in average levels of NA in the days following the task compared to the days preceding it. Our findings suggest that laboratory stress tasks may pose a significant risk to more vulnerable individuals.