Design of effective personalised perturbation strategies for enhancing cognitive intervention in Alzheimer’s disease

One of the potential and promising adjuvant therapies for Alzheimer’s disease is that of non-invasive transcranial neurostimulation to potentiate cognitive training interventions. Conceptually, this is achieved by driving brain dynamics towards an optimal state for an effective facilitation of cognitive training interventions. However, current neurostimulation protocols rely on experimental trial-and-error approaches that result in variability of symptom improvements and suboptimal progress. Here, we leveraged whole-brain computational modelling by assessing the regional susceptibility towards optimal brain dynamics from Alzheimer’s disease. In practice, we followed the three-part concept of Dynamic Sensitivity Analysis by first understanding empirical differences between healthy controls and patients with mild cognitive impairment and mild dementia due to Alzheimer’s Disease; secondly, by building computational models for all individuals in the mild cognitive impairment and mild dementia cohorts; and thirdly, by perturbing brain regions and assessing the impact on the recovery of brain dynamics to the healthy state (here defined in functional terms, summarised by a measure of metastability for the healthy group). By doing so, we show the importance of key regions, along the anterior-posterior medial line, in driving in-silico improvement of mild dementia and mild cognitive impairment groups. Moreover, this subset consists mainly of regions with high structural nodal degree. Overall, this in-silico perturbational approach could inform the design of stimulation strategies for re-establishing healthy brain dynamics, putatively facilitating effective cognitive interventions targeting the cognitive decline in Alzheimer’s disease

Hierarchical heterogeneity across human cortex shapes large-scale neural dynamics

The large-scale organization of dynamical neural activity across cortex emerges through long-range interactions among local circuits. We hypothesized that large-scale dynamics are also shaped by heterogeneity of intrinsic local properties across cortical areas. One key axis along which microcircuit properties are specialized relates to hierarchical levels of cortical organization. We developed a large-scale dynamical circuit model of human cortex that incorporates heterogeneity of local synaptic strengths, following a hierarchical axis inferred from MRI-derived T1w/T2w mapping, and fit the model using multimodal neuroimaging data. We found that incorporating hierarchical heterogeneity substantially improves the model fit to fMRI-measured resting-state functional connectivity and captures sensory-association organization of multiple fMRI features. The model predicts hierarchically organized high-frequency spectral power, which we tested with resting-state magnetoencephalography. These findings suggest circuit-level mechanisms linking spatiotemporal levels of analysis and highlight the importance of local properties and their hierarchical specialization on the large-scale organization of human cortical dynamics

Investigation of the Protective Effects of Dexmedetomidine, Midazolam, Propofol, and Intralipid on Oxidative Stress and Inflammation in Rats with Lidocaine-Induced Toxicity

Mustafa Kemal Kucun,1 Eray Metin Guler,2,3 Ayten Saracoglu,4 Mehmet Yildirim,5 Cumaali Demirtas,5 Ferda Serdogan,6 Hakan Beyaztas,2,7 Selman Aktas,8 Merve Kacan,9 Tomasz Gaszynski,10 Pawel Ratajczyk,10 Kemal Tolga Saracoglu11 1Department of Anesthesiology and Intensive Care, Bartin State Hospital, Bartin, Turkey; 2Department of Medical Biochemistry, Hamidiye Faculty of Medicine, University of Health Sciences Turkey, Istanbul, Türkiye; 3Department of Medical Biochemistry, Hamidiye Institute of Health Sciences, University of Health Sciences Turkey, Istanbul, Türkiye; 4Department of Anesthesiology, ICU & Perioperative Medicine Aisha Bint Hamad Al Attiyah Hospital HMC, Doha, Qatar; 5Department of Physiology, Hamidiye Faculty of Medicine, University of Health Sciences, Istanbul, Turkey; 6Department of Anesthesiology and Intensive Care, Turhal State Hospital, Tokat, Turkey; 7Department of Medical Biochemistry, HaydarpasaNumune Health Application and Research Center, University of Health Sciences Turkey, Istanbul, Türkiye; 8University of Health Sciences, Hamidiye Faculty of Medicine, Department of Biostatistics and Medical Informatics, Istanbul, Turkey; 9Department of Anesthesiology and Intensive Care, Kocaeli City Hospital, Kocaeli, Turkey; 10Department of Anesthesiology and Intensive Therapy, Medical University of Lodz, Lodz, Poland; 11Department of Anesthesiology, ICU & Perioperative Medicine Hazm Mebaireek General Hospital HMC, Industrial Area Ar-Rayyan, Doha, QatarCorrespondence: Mustafa Kemal Kucun, Department of Anesthesiology and Intensive Care, Bart&inodot;n State Hospital, Bart&inodot;n, Turkey, Email [email protected]: The aim of this study was to compare the effects of dexmedetomidine, midazolam, propofol, and intralipid on lidocaine-induced cardiotoxicity and neurotoxicity.Methods: Forty-eight male Sprague-Dawley rats were randomly divided into six groups (n = 8 per group): control (C), lidocaine (L), lidocaine + dexmedetomidine (LD), lidocaine + midazolam (LM), lidocaine + propofol (LP), and lidocaine + intralipid (LI). Dexmedetomidine (100 μg/kg), midazolam (4 mg/kg), propofol (40 mg/kg), and intralipid (10 mg/kg) were administered intraperitoneally as pretreatment. Lidocaine (90 mg/kg) was administered intraperitoneally to induce oxidative stress in all groups except the control. After 60 minutes of electrocardiography (ECG) recording, the rats were sacrificed, and heart and brain tissue samples were collected. Comparative measurements of total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and inflammatory parameters were conducted.Results: In heart tissue samples, TAS was significantly higher in LI and LD groups (p < 0.05). Additionally, oxidative stress was significantly higher in the LM group (p < 0.05). Despite an increase in oxidative stress in brain tissue samples across all groups, it was found that all groups exhibited antioxidant protective effects (p < 0.05). Inflammatory parameters in heart and brain tissues significantly decreased in all groups, especially in the LI group (p < 0.05).Conclusion: It was observed that pretreatment with midazolam increased oxidative stress induced by lidocaine, while dexmedetomidine and intralipid exhibited greater antioxidant effects. Dexmedetomidine and intralipid used as pretreatment were shown to be more effective in protecting against oxidative stress and inflammation.Keywords: oxidative stress, inflammation, dexmedetomidine, midazolam, propofol, intralipi

Perceived leader integrity as a mediator between ethical leadership and ethical climate in a teaching context

Background: Scandalous incidents occurring in prominent organisations in the world have brought to limelight the role of leaders in shaping the ethical climate of their organisations. As a result, several studies across different organisational/occupational contexts and climes have examined and unanimously proven that ethical leadership was positively related to ethical climate. However, there is rarely any of these studies that was conducted in teaching context. Besides, the mechanisms involved between ethical leadership and ethical climate seems not to have been addressed in literature. Thus, this paper reports the findings of a study that investigated the mediating role of perceived leader integrity in the ethical leadership-ethical climate relationship among teachers. Methods: Data were collected from 336 teachers (105 male and 231 female) in three-time periods using measures of ethical leadership, perceived leader integrity, ethical climate, and demographics. Results: The results from OLS regression-based path analysis showed that: 1) ethical leadership was positively related to perceived leader integrity, 2) perceived leader integrity was positively related to ethical climate, 3) ethical leadership was positively related to ethical climate, and 4) the positive relationship between ethical leadership and ethical climate was mediated by perceived leader integrity. Conclusions: The current study extends the social learning theory by identifying perceived leader integrity as a mechanism underlying the relationship between ethical leadership and ethical climate. The findings have some implications for personnel selection especially in relation to selection of ethical leaders.</p

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Studies of a Ring-Cleaving Dioxygenase Illuminate the Role of Cholesterol Metabolism in the Pathogenesis of Mycobacterium tuberculosis

Mycobacterium tuberculosis, the etiological agent of TB, possesses a cholesterol catabolic pathway implicated in pathogenesis. This pathway includes an iron-dependent extradiol dioxygenase, HsaC, that cleaves catechols. Immuno-compromised mice infected with a ΔhsaC mutant of M. tuberculosis H37Rv survived 50% longer than mice infected with the wild-type strain. In guinea pigs, the mutant disseminated more slowly to the spleen, persisted less successfully in the lung, and caused little pathology. These data establish that, while cholesterol metabolism by M. tuberculosis appears to be most important during the chronic stage of infection, it begins much earlier and may contribute to the pathogen's dissemination within the host. Purified HsaC efficiently cleaved the catecholic cholesterol metabolite, DHSA (3,4-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione; kcat/Km = 14.4±0.5 µM−1 s−1), and was inactivated by a halogenated substrate analogue (partition coefficient<50). Remarkably, cholesterol caused loss of viability in the ΔhsaC mutant, consistent with catechol toxicity. Structures of HsaC:DHSA binary complexes at 2.1 Å revealed two catechol-binding modes: bidentate binding to the active site iron, as has been reported in similar enzymes, and, unexpectedly, monodentate binding. The position of the bicyclo-alkanone moiety of DHSA was very similar in the two binding modes, suggesting that this interaction is a determinant in the initial substrate-binding event. These data provide insights into the binding of catechols by extradiol dioxygenases and facilitate inhibitor design