Systematic Electronic Tuning on the Property and Reactivity of Cobalt-(Hydro)peroxo Intermediates.

A series of cobalt(III)-peroxo complexes, [CoIII(R2-TBDAP)(O2)]+ (1R2; R2 = Cl, H, and OMe), and cobalt(III)-hydroperoxo complexes, [CoIII(R2-TBDAP)(O2H)(CH3CN)]2+ (2R2), bearing electronically tuned tetraazamacrocyclic ligands (R2-TBDAP = N,N'-di-tert-butyl-2,11-diaza[3.3](2,6)-p-R2-pyridinophane) were prepared from their cobalt(II) precursors and characterized by various physicochemical methods. The X-ray diffraction and spectroscopic analyses unambiguously showed that all 1R2 compounds have similar octahedral geometry with a side-on peroxocobalt(III) moiety, but the O-O bond lengths of 1Cl [1.398(3) Å] and 1OMe [1.401(4) Å] were shorter than that of 1H [1.456(3) Å] due to the different spin states. For 2R2, the O-O bond vibration energies of 2Cl and 2OMe were identical at 853 cm-1 (856 cm-1 for 2H), but their Co-O bond vibration frequencies were observed at 572 cm-1 for 2Cl and 550 cm-1 for 2OMe, respectively, by resonance Raman spectroscopy (560 cm-1 for 2H). Interestingly, the redox potentials (E1/2) of 2R2 increased in the order of 2OMe (0.19 V) < 2H (0.24 V) < 2Cl (0.34 V) according to the electron richness of the R2-TBDAP ligands, but the oxygen-atom-transfer reactivities of 2R2 showed a reverse trend (k2: 2Cl < 2H < 2OMe) with a 13-fold rate enhancement at 2OMe over 2Cl in a sulfoxidation reaction with thioanisole. Although the reactivity trend contradicts the general consideration that electron-rich metal-oxygen species with low E1/2 values have sluggish electrophilic reactivity, this could be explained by a weak Co-O bond vibration of 2OMe in the unusual reaction pathway. These results provide considerable insight into the electronic nature-reactivity relationship of metal-oxygen species.

Neural activation underlying emotional interference of cognitive control in rotating shift workers: moderating effects of the prefrontal cortex response on the association between sleep disturbance and depressive symptoms.

STUDY OBJECTIVES: This study investigated the altered neural function involved in emotional interference and its role in linking sleep disturbance and depressive/anxiety symptoms in rotating shift workers. METHODS: Sixty rotating shift workers and 61 controls performed the emotional Stroop task in three blocks (emotional-related, sleep-related, and neutral words) during functional magnetic resonance imaging (fMRI) assessments. Sleep disturbance and depressive/anxiety symptoms were assessed using self-report measures and sleep diaries. Actigraphy was used to assess the sleep and circadian variables. fMRI scans were performed to compare brain activation during the emotional Stroop task. The proposed moderating models were tested using the PROCESS macro in SPSS software. RESULTS: A significant condition effect on reaction time was detected. Regardless of the group, reaction times were longer in the negative emotional word and sleep-related conditions than in the neutral word condition. Whole-brain analysis revealed that rotating shift workers show greater neural activation in the left dorsolateral prefrontal cortex (DLPFC) compared with controls while performing the emotional Stroop task with negative emotional words. Sleep disturbance was more strongly associated with depressive symptoms when activation of the left DLPFC was higher during the emotional Stroop task with negative words. CONCLUSIONS: The left DLPFC may play important roles in increased sensitivity to emotional information, possibly due to circadian misalignment, and has moderating effects on the association between sleep disturbance and depressive symptoms in rotating shift workers. These findings will help to identify possible brain regions where interventions can be performed to correct sleep and mood problems in rotating shift workers.

Negative life stress, sleep disturbance, and depressive symptoms: The moderating role of anterior insula activity in response to sleep-related stimuli.

BACKGROUND: This study investigated the effects of anterior insula (AI) activation on the association between stress and sleep disturbance as a neurobiological basis of the trait-like degree of sleep reactivity to stress. Additionally, it examined the effects of AI activity on the association between sleep disturbance and depression. METHODS: The participants were 48 adults. To assess AI activation in response to sleep-related stimuli (SS) compared to neutral stimuli (NS), we extracted mean AI parameter estimates for the SS-NS contrast. We examined whether the interaction between life stress and AI activation would predict sleep disturbance and whether the interaction between sleep disturbance and AI activation would predict depression. RESULTS: At higher levels of bilateral AI activation in response to SS, higher levels of stress were associated with greater sleep disturbance (left AI x stress: b = 1.07, SE = 0.44, p < 0.05; right AI x stress: b = 1.05, SE = 0.48, p < 0.05). In addition, at higher levels of right AI activation, higher levels of sleep disturbance were associated with more severe depressive symptoms (right AI x sleep disturbance: b = 2.55, SE = 1.10, p < 0.05). LIMITATION: This study assessed sleep quality and depressive symptoms based on self-reported questionnaires. CONCLUSION: This study revealed moderating effects of AI activation on the association between negative life stress and sleep disturbance. Additionally, AI activation strengthened the association between sleep disturbance and depression. AI activation may reflect a crucial etiological diathesis for insomnia and stress-related disorders.

Association between snoring and heart rate variability in adolescents: effects of gender and insufficient sleep.

PURPOSE: We explored the association between subjective snoring frequency and heart rate variability (HRV) in a healthy adolescent population. METHODS: A total of 102 healthy adolescents were recruited from high schools in South Korea, and reported their sleep habits and snoring frequency. HRV was assessed to indirectly measure autonomic function. We assessed correlations between snoring frequency and HRV indices. We also investigated the effects of sex and behaviorally induced insufficient sleep syndrome (BISS) on the associations between HRV parameters and snoring frequency. RESULTS: Overall, significant correlations were apparent between snoring frequency and HRV indices including the standard deviation of the normal-to-normal intervals (SDNN) and the low-frequency/high-frequency (LF/HF) ratio. Associations were more evident in males and those with BISS compared to females and those without BISS. CONCLUSIONS: Our findings suggest that snoring changes autonomic nervous system (ANS) activity in adolescents; the changes are more dramatic in males and those with insufficient sleep.

Cancer-Stimulated CAFs Enhance Monocyte Differentiation and Protumoral TAM Activation via IL6 and GM-CSF Secretion.

Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network.Experimental Design: Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database.Results: Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell-activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data.Conclusions: Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the "henchmen" for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. Clin Cancer Res; 24(21); 5407-21. ©2018 AACR.