Targeting mitochondrial bioenergetics by combination treatment with imatinib and dichloroacetate in human erythroleukemic K­562 and colorectal HCT­116 cancer cells.

Tumor malignant cells are characterized by dysregulation of mitochondrial bioenergetics due to the 'Warburg effect'. In the present study, this metabolic imbalance was explored as a potential target for novel cancer chemotherapy. Imatinib (IM) downregulates the expression levels of SCΟ2 and FRATAXIN (FXN) genes involved in the heme­dependent cytochrome c oxidase biosynthesis and assembly pathway in human erythroleukemic IM­sensitive K­562 chronic myeloid leukemia cells (K­562). In the present study, it was investigated whether the treatment of cancer cells with IM (an inhibitor of oxidative phosphorylation) separately, or together with dichloroacetate (DCA) (an inhibitor of glycolysis), can inhibit cell proliferation or cause death. Human K­562 and IM­chemoresistant K­562 chronic myeloid leukemia cells (K­562R), as well as human colorectal carcinoma cells HCT­116 (+/+p53) and (­/­p53, with double TP53 knock-in disruptions), were employed. Treatments of these cells with either IM (1 or 2 µM) and/or DCA (4 mΜ) were also assessed for the levels of several process biomarkers including SCO2, FXN, lactate dehydrogenase A, glyceraldehyde­3­phosphate dehydrogenase, pyruvate kinase M2, hypoxia inducing factor­1a, heme oxygenase­1, NF­κB, stem cell factor and vascular endothelial growth factor via western blot analysis. Computational network biology models were also applied to reveal the connections between the ten proteins examined. Combination treatment of IM with DCA caused extensive cell death (>75%) in K­562 and considerable (>45%) in HCT­116 (+/+p53) cultures, but less in K­562R and HCT­116 (­/­p53), with the latter deficient in full length p53 protein. Such treatment, markedly reduced reactive oxygen species levels, as measured by flow­cytometry, in K­562 cells and affected the oxidative phosphorylation and glycolytic biomarkers in all lines examined. These findings indicated, that targeting of cancer mitochondrial bioenergetics with such a combination treatment was very effective, although chemoresistance to IM in leukemia and the absence of a full length p53 in colorectal cells affected its impact.

Magnetic Resonance Spectroscopy (MRS) in Alzheimer's Disease.

MRS is a noninvasive technique to measure different metabolites in the brain. Changes in the levels of certain metabolites can be used as surrogate markers for Alzheimer's disease. They can potentially be used for diagnosis, prediction of prognosis, or even assessing response to treatment.There are different techniques for MRS acquisitions including STimulated Echo Acquisition Mode (STEAM) and Point Resolved Spectroscopy (PRESS). In terms of localization, single or multi-voxel methods can be used. Based on current data: 1. NAA, marker of neuronal integrity and viability, reduces in AD with longitudinal changes over the time as the disease progresses. There are data claiming that reduction of NAA is associated with tau accumulation, early neurodegenerative processes, and cognitive decline. Therefore, it can be used as a stage biomarker for AD to assess the severity of the disease. With advancement of disease modifying therapies, there is a potential role for NAA in the future to be used as a marker of response to treatment. 2. mI, marker of glial cell proliferation and activation, is associated with AB pathology and has early changes in the course of the disease. The NAA/mI ratio can be predictive of AD development with high specificity and can be utilized in the clinical setting to stratify cases for further evaluation with PET for potential treatments. 3. The changes in the level of other metabolites such as Chol, Glu, Gln, and GABA are controversial because of the lack of standardization of MRS techniques, current technical limitations, and possible region specific changes. 4. Ultrahigh field MRS and more advanced techniques can overcome many of these limitations and enable us to measure more metabolites with higher accuracy. 5. Standardization of MRS techniques, validation of metabolites' changes against PET using PET-guided technique, and longitudinal follow-ups to investigate the temporal changes of the metabolites in relation to other biomarkers and cognition will be crucial to confirm the utility of MRS as a potential noninvasive biomarker for AD.

The driving force behind tool-stone selection in the African Middle Stone Age.

In the Stone Age, the collection of specific rocks was the first step in tool making. Very little is known about the choices made during tool-stone acquisition. Were choices governed by the knowledge of, and need for, specific properties of stones? Or were the collected raw materials a mere by-product of the way people moved through the landscape? We investigate these questions in the Middle Stone Age (MSA) of southern Africa, analyzing the mechanical properties of tool-stones used at the site Diepkloof Rock Shelter. To understand knapping quality, we measure flaking predictability and introduce a physical model that allows calculating the relative force necessary to produce flakes from different rocks. To evaluate their quality as finished tools, we investigate their resistance during repeated use activities (scraping or cutting) and their strength during projectile impacts. Our findings explain tool-stone selection in two emblematic periods of the MSA, the Still Bay and Howiesons Poort, as being the result of a deep understanding of these mechanical properties. In both cases, people chose those rocks, among many others, that allowed the most advantageous trade-off between anticipated properties of finished tools and the ease of acquiring rocks and producing tools. The implications are an understanding of African MSA toolmakers as engineers who carefully weighed their choices taking into account workability and the quality of the tools they made.

Cortical timescales and the modular organization of structural and functional brain networks.

Recent years have seen growing interest in characterizing the properties of regional brain dynamics and their relationship to other features of brain structure and function. In particular, multiple studies have observed regional differences in the "timescale" over which activity fluctuates during periods of quiet rest. In the cerebral cortex, these timescales have been associated with both local circuit properties as well as patterns of inter-regional connectivity, including the extent to which each region exhibits widespread connectivity to other brain areas. In the current study, we build on prior observations of an association between connectivity and dynamics in the cerebral cortex by investigating the relationship between BOLD fMRI timescales and the modular organization of structural and functional brain networks. We characterize network community structure across multiple scales and find that longer timescales are associated with greater within-community functional connectivity and diverse structural connectivity. We also replicate prior observations of a positive correlation between timescales and structural connectivity degree. Finally, we find evidence for preferential functional connectivity between cortical areas with similar timescales. We replicate these findings in an independent dataset. These results contribute to our understanding of functional brain organization and structure-function relationships in the human brain, and support the notion that regional differences in cortical dynamics may in part reflect the topological role of each region within macroscale brain networks.

Protocol for teen inflammation glutamate emotion research (TIGER): Toward predictors of treatment response and clinical course in depressed adolescents.

Adolescent-onset depression is a prevalent and debilitating condition commonly associated with treatment refractory depression and non-response to first-line antidepressants. There are, however, no objective tests to determine who may or may not respond to antidepressants. As depressed adolescents are especially vulnerable to the lifelong consequences of ineffectively-treated depression, it is critical to identify neurobiological predictors of treatment non-response in this population. Here, we describe the scientific rationale and protocol for the Teen Inflammation Glutamate Emotion Research (TIGER) study, a prospective 18-month investigation of 160 depressed adolescents who will be assessed before and after treatment with selective serotonin reuptake inhibitors. TIGER will be using ultra-high field imaging to test the effects of acute stress and antidepressant treatment on inflammatory and glutamatergic processes hypothesized to underlie depression maintenance. Results from this work will motivate future studies testing alternative therapeutics for depressed adolescents at risk for treatment resistant depression. ClinicalTrials.gov Identifier: NCT05329441.

Age-Related Decline in Blood-Brain Barrier Function is More Pronounced in Males than Females in Parietal and Temporal Regions.

The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), shielding it from potential harmful entities. A natural decline of BBB function with aging has been reported in both animal and human studies, which may contribute to cognitive decline and neurodegenerative disorders. Limited data also suggest that being female may be associated with protective effects on BBB function. Here we investigated age and sex-dependent trajectories of perfusion and BBB water exchange rate (kw) across the lifespan in 186 cognitively normal participants spanning the ages of 8 to 92 years old, using a non-invasive diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI technique. We found that the pattern of BBB kw decline with aging varies across brain regions. Moreover, results from our DP-pCASL technique revealed a remarkable decline in BBB kw beginning in the early 60s, which was more pronounced in males. In addition, we observed sex differences in parietal and temporal regions. Our findings provide in vivo results demonstrating sex differences in the decline of BBB function with aging, which may serve as a foundation for future investigations into perfusion and BBB function in neurodegenerative and other brain disorders.

Cerebral perfusion in post-stroke aphasia and its relationship to residual language abilities.

Stroke alters blood flow to the brain resulting in damaged tissue and cell death. Moreover, the disruption of cerebral blood flow (perfusion) can be observed in areas surrounding and distal to the lesion. These structurally preserved but suboptimally perfused regions may also affect recovery. Thus, to better understand aphasia recovery, the relationship between cerebral perfusion and language needs to be systematically examined. In the current study, we aimed to evaluate (i) how stroke affects perfusion outside of lesioned areas in chronic aphasia and (ii) how perfusion in specific cortical areas and perilesional tissue relates to language outcomes in aphasia. We analysed perfusion data from a large sample of participants with chronic aphasia due to left hemisphere stroke (n = 43) and age-matched healthy controls (n = 25). We used anatomically defined regions of interest that covered the frontal, parietal, and temporal areas of the perisylvian cortex in both hemispheres, areas typically known to support language, along with several control regions not implicated in language processing. For the aphasia group, we also looked at three regions of interest in the perilesional tissue. We compared perfusion levels between the two groups and investigated the relationship between perfusion levels and language subtest scores while controlling for demographic and lesion variables. First, we observed that perfusion levels outside the lesioned areas were significantly reduced in frontal and parietal regions in the left hemisphere in people with aphasia compared to the control group, while no differences were observed for the right hemisphere regions. Second, we found that perfusion in the left temporal lobe (and most strongly in the posterior part of both superior and middle temporal gyri) and inferior parietal areas (supramarginal gyrus) was significantly related to residual expressive and receptive language abilities. In contrast, perfusion in the frontal regions did not show such a relationship; no relationship with language was also observed for perfusion levels in control areas and all right hemisphere regions. Third, perilesional perfusion was only marginally related to language production abilities. Cumulatively, the current findings demonstrate that blood flow is reduced beyond the lesion site in chronic aphasia and that hypoperfused neural tissue in critical temporoparietal language areas has a negative impact on behavioural outcomes. These results, using perfusion imaging, underscore the critical and general role that left hemisphere posterior temporal regions play in various expressive and receptive language abilities. Overall, the study highlights the importance of exploring perfusion measures in stroke.

Dopamine Modulates Effective Connectivity in Frontal Cortex.

There is increasing evidence that the left lateral frontal cortex is hierarchically organized such that higher-order regions have an asymmetric top-down influence over lower order regions. However, questions remain about the underlying neuroarchitecture of this hierarchical control organization. Within the frontal cortex, dopamine plays an important role in cognitive control functions, and we hypothesized that dopamine may preferentially influence top-down connections within the lateral frontal hierarchy. Using a randomized, double-blind, within-subject design, we analyzed resting-state fMRI data of 66 healthy young participants who were scanned once each after administration of bromocriptine (a dopamine agonist with preferential affinity for D2 receptor), tolcapone (an inhibitor of catechol-O-methyltransferase), and placebo, to determine whether dopaminergic stimulation modulated effective functional connectivity between hierarchically organized frontal regions in the left hemisphere. We found that dopaminergic drugs modulated connections from the caudal middle frontal gyrus and the inferior frontal sulcus to both rostral and caudal frontal areas. In dorsal frontal regions, effectivity connectivity strength was increased, whereas in ventral frontal regions, effective connectivity strength was decreased. These findings suggest that connections within frontal cortex are differentially modulated by dopamine, which may bias the influence that frontal regions exert over each other.

Recruiting In Vitro Transcribed mRNA against Cancer Immunotherapy: A Contemporary Appraisal of the Current Landscape.

Over 100 innovative in vitro transcribed (IVT)-mRNAs are presently undergoing clinical trials, with a projected substantial impact on the pharmaceutical market in the near future. Τhe idea behind this is that after the successful cellular internalization of IVT-mRNAs, they are subsequently translated into proteins with therapeutic or prophylactic relevance. Simultaneously, cancer immunotherapy employs diverse strategies to mobilize the immune system in the battle against cancer. Therefore, in this review, the fundamental principles of IVT-mRNA to its recruitment in cancer immunotherapy, are discussed and analyzed. More specifically, this review paper focuses on the development of mRNA vaccines, the exploitation of neoantigens, as well as Chimeric Antigen Receptor (CAR) T-Cells, showcasing their clinical applications and the ongoing trials for the development of next-generation immunotherapeutics. Furthermore, this study investigates the synergistic potential of combining the CAR immunotherapy and the IVT-mRNAs by introducing our research group novel, patented delivery method that utilizes the Protein Transduction Domain (PTD) technology to transduce the IVT-mRNAs encoding the CAR of interest into the Natural Killer (NK)-92 cells, highlighting the potential for enhancing the CAR NK cell potency, efficiency, and bioenergetics. While IVT-mRNA technology brings exciting progress to cancer immunotherapy, several challenges and limitations must be acknowledged, such as safety, toxicity, and delivery issues. This comprehensive exploration of IVT-mRNA technology, in line with its applications in cancer therapeutics, offers valuable insights into the opportunities and challenges in the evolving landscape of cancer immunotherapy, setting the stage for future advancements in the field.

Cortical timescales and the modular organization of structural and functional brain networks.

Recent years have seen growing interest in characterizing the properties of regional brain dynamics and their relationship to other features of brain structure and function. In particular, multiple studies have observed regional differences in the "timescale" over which activity fluctuates during periods of quiet rest. In the cerebral cortex, these timescales have been associated with both local circuit properties as well as patterns of inter-regional connectivity, including the extent to which each region exhibits widespread connectivity to other brain areas. In the current study, we build on prior observations of an association between connectivity and dynamics in the cerebral cortex by investigating the relationship between BOLD fMRI timescales and the modular organization of structural and functional brain networks. We characterize network community structure across multiple scales and find that longer timescales are associated with greater within-community functional connectivity and diverse structural connectivity. We also replicate prior observations of a positive correlation between timescales and structural connectivity degree. Finally, we find evidence for preferential functional connectivity between cortical areas with similar timescales. We replicate these findings in an independent dataset. These results contribute to our understanding of functional brain organization and structure-function relationships in the human brain, and support the notion that regional differences in cortical dynamics may in part reflect the topological role of each region within macroscale brain networks.

The pursuit of approaches to federate data to accelerate Alzheimer's disease and related dementia research: GAAIN, DPUK, and ADDI.

There is common consensus that data sharing accelerates science. Data sharing enhances the utility of data and promotes the creation and competition of scientific ideas. Within the Alzheimer's disease and related dementias (ADRD) community, data types and modalities are spread across many organizations, geographies, and governance structures. The ADRD community is not alone in facing these challenges, however, the problem is even more difficult because of the need to share complex biomarker data from centers around the world. Heavy-handed data sharing mandates have, to date, been met with limited success and often outright resistance. Interest in making data Findable, Accessible, Interoperable, and Reusable (FAIR) has often resulted in centralized platforms. However, when data governance and sovereignty structures do not allow the movement of data, other methods, such as federation, must be pursued. Implementation of fully federated data approaches are not without their challenges. The user experience may become more complicated, and federated analysis of unstructured data types remains challenging. Advancement in federated data sharing should be accompanied by improvement in federated learning methodologies so that federated data sharing becomes functionally equivalent to direct access to record level data. In this article, we discuss federated data sharing approaches implemented by three data platforms in the ADRD field: Dementia's Platform UK (DPUK) in 2014, the Global Alzheimer's Association Interactive Network (GAAIN) in 2012, and the Alzheimer's Disease Data Initiative (ADDI) in 2020. We conclude by addressing open questions that the research community needs to solve together.

Comparison of genetic and health risk factors for mild cognitive impairment and Alzheimer's disease between Hispanic and non-Hispanic white participants.

INTRODUCTION: The influence of apolipoprotein E (APOE) genotype on mild cognitive impairment (MCI) and Alzheimer's disease (AD) is well studied in the non-Hispanic white (NHW) population but not in the Hispanic population. Additionally, health risk factors such as hypertension, stroke, and depression may also differ between the two populations. METHODS: We combined three data sets (National Alzheimer's Coordinating Center [NACC], Alzheimer's Disease Neuroimaging Initiative [ADNI], Health and Aging Brain Study: Health Disparities [HABS-HD]) and compared risk factors for MCI and AD between Hispanic and NHW participants, with a total of 24,268 participants (11.1% Hispanic). RESULTS: APOEε4 was associated with fewer all-cause MCI cases in Hispanic participants (Hispanic odds ratio [OR]: 1.114; NHW OR: 1.453), and APOEε2 (Hispanic OR: 1.224; NHW OR: 0.592) and depression (Hispanic OR: 2.817; NHW OR: 1.847) were associated with more AD cases in Hispanic participants. DISCUSSION: APOEε2 may not be protective for AD in Hispanic participants and Hispanic participants with depression may face a higher risk for AD. HIGHLIGHTS: GAAIN allows for discovery of data sets to use in secondary analyses. APOEε2 was not protective for AD in Hispanic participants. APOEε4 was associated with fewer MCI cases in Hispanic participants. Depression was associated with more AD cases in Hispanic participants.

Decreased functional connectivity is associated with increased levels of Cerebral Spinal Fluid soluble-PDGFRß, a marker of blood brain barrier breakdown, in older adults.

Resting-state functional connectivity (FC) is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. For instance, studies in pre-clinical AD subjects have shown increases of cerebral spinal fluid soluble platelet-derived growth factor receptor-ß (CSF sPDGFRß, a marker of BBB breakdown) but have not demonstrated if this vascular impairment affects neuronal dysfunction. It's possible that increased levels of sPDGFRß in the CSF may correlate with impaired FC in metabolically demanding brain regions (i.e. Default Mode Network, DMN). Our study aimed to investigate the relationship between these two markers in older individuals that were cognitively normal and had cognitive impairment. Eighty-nine older adults without dementia from the University of Southern California were selected from a larger cohort. Region of interest (ROI) to ROI analyses were conducted using DMN seed regions. Linear regression models measured significant associations between BOLD FC strength among seed-target regions and sPDGFRß values, while covarying for age and sex. Comparison of a composite ROI created by averaging FC values between seed and all target regions among cognitively normal and impaired individuals was also examined. Using CSF sPDGFRß as a biomarker of BBB breakdown, we report that increased breakdown correlated with decreased functional connectivity in DMN areas, specifically the PCC while the hippocampus exhibited an interaction effect using CDR score. We conclude that BBB breakdown as measured by CSF sPDGFRß affects neural networks resulting in decreased functional connections that leads to cognitive dysfunction.

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency.

Mitochondrial disorders represent a heterogeneous group of genetic disorders with variations in severity and clinical outcomes, mostly characterized by respiratory chain dysfunction and abnormal mitochondrial function. More specifically, mutations in the human SCO2 gene, encoding the mitochondrial inner membrane Sco2 cytochrome c oxidase (COX) assembly protein, have been implicated in the mitochondrial disorder fatal infantile cardioencephalomyopathy with COX deficiency. Since an effective treatment is still missing, a protein replacement therapy (PRT) was explored using protein transduction domain (PTD) technology. Therefore, the human recombinant full-length mitochondrial protein Sco2, fused to TAT peptide (a common PTD), was produced (fusion Sco2 protein) and successfully transduced into fibroblasts derived from a SCO2/COX-deficient patient. This PRT contributed to effective COX assembly and partial recovery of COX activity. In mice, radiolabeled fusion Sco2 protein was biodistributed in the peripheral tissues of mice and successfully delivered into their mitochondria. Complementary to that, an mRNA-based therapeutic approach has been more recently considered as an innovative treatment option. In particular, a patented, novel PTD-mediated IVT-mRNA delivery platform was developed and applied in recent research efforts. PTD-IVT-mRNA of full-length SCO2 was successfully transduced into the fibroblasts derived from a SCO2/COX-deficient patient, translated in host ribosomes into a nascent chain of human Sco2, imported into mitochondria, and processed to the mature protein. Consequently, the recovery of reduced COX activity was achieved, thus suggesting the potential of this mRNA-based technology for clinical translation as a PRT for metabolic/genetic disorders. In this review, such research efforts will be comprehensibly presented and discussed to elaborate their potential in clinical application and therapeutic usefulness.

Distributed harmonic patterns of structure-function dependence orchestrate human consciousness.

A central question in neuroscience is how consciousness arises from the dynamic interplay of brain structure and function. Here we decompose functional MRI signals from pathological and pharmacologically-induced perturbations of consciousness into distributed patterns of structure-function dependence across scales: the harmonic modes of the human structural connectome. We show that structure-function coupling is a generalisable indicator of consciousness that is under bi-directional neuromodulatory control. We find increased structure-function coupling across scales during loss of consciousness, whether due to anaesthesia or brain injury, capable of discriminating between behaviourally indistinguishable sub-categories of brain-injured patients, tracking the presence of covert consciousness. The opposite harmonic signature characterises the altered state induced by LSD or ketamine, reflecting psychedelic-induced decoupling of brain function from structure and correlating with physiological and subjective scores. Overall, connectome harmonic decomposition reveals how neuromodulation and the network architecture of the human connectome jointly shape consciousness and distributed functional activation across scales.

Understanding recovery of language after stroke: insights from neurovascular MRI studies.

Stroke causes a disruption in blood flow to the brain that can lead to profound language impairments. Understanding the mechanisms of language recovery after stroke is crucial for the prognosis and effective rehabilitation of people with aphasia. While the role of injured brain structures and disruptions in functional connectivity have been extensively explored, the relationship between neurovascular measures and language recovery in both early and later stages has not received sufficient attention in the field. Fully functioning healthy brain tissue requires oxygen and nutrients to be delivered promptly via its blood supply. Persistent decreases in blood flow after a stroke to the remaining non-lesioned tissue have been shown to contribute to poor language recovery. The goal of the current paper is to critically examine stroke studies looking at the relationship between different neurovascular measures and language deficits and mechanisms of language recovery via changes in neurovascular metrics. Measures of perfusion or cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) provide complementary approaches to understanding neurovascular mechanisms post stroke by capturing both cerebral metabolic demands and mechanical vascular properties. While CBF measures indicate the amount of blood delivered to a certain region and serve as a proxy for metabolic demands of that area, CVR indices reflect the ability of the vasculature to recruit blood flow in response to a shortage of oxygen, such as when one is holding their breath. Increases in CBF during recovery beyond the site of the lesion have been shown to promote language gains. Similarly, CVR changes, when collateral vessels are recruited to help reorganize the flow of blood in hypoperfused regions, have been related to functional recovery post stroke. In the current review, we highlight the main findings in the literature investigating neurovascular changes in stroke recovery with a particular emphasis on how language abilities can be affected by changes in CBF and CVR. We conclude by summarizing existing methodological challenges and knowledge gaps that need to be addressed in future work in this area, outlining a promising avenue of research.

An Innovative PTD-IVT-mRNA Delivery Platform for CAR Immunotherapy of ErbB(+) Solid Tumor Neoplastic Cells.

Chimeric antigen receptor (CAR) immunotherapy includes the genetic modification of immune cells to carry such a receptor and, thus, recognize cancer cell surface antigens. Viral transfection is currently the preferred method, but it carries the risk of off-target mutagenicity. Other transfection platforms have thus been proposed, such the in vitro transcribed (IVT)-mRNAs. In this study, we exploited our innovative, patented delivery platform to produce protein transduction domain (PTD)-IVT-mRNAs for the expression of CAR on NK-92 cells. CAR T1E-engineered NK-92 cells, harboring the sequence of T1E single-chain fragment variant (scFv) to recognize the ErbB receptor, bearing either CD28 or 4-1BB as co-stimulatory signaling domains, were prepared and assessed for their effectiveness in two different ErbB(+) cancer cell lines. Our results showed that the PTD-IVT-mRNA of CAR was safely transduced and expressed into NK-92 cells. CAR T1E-engineered NK-92 cells provoked high levels of cell death (25-33%) as effector cells against both HSC-3 (oral squamous carcinoma) and MCF-7 (breast metastatic adenocarcinoma) human cells in the co-incubation assays. In conclusion, the application of our novel PTD-IVT-mRNA delivery platform to NK-92 cells gave promising results towards future CAR immunotherapy approaches.

Consciousness is supported by near-critical slow cortical electrodynamics.

Mounting evidence suggests that during conscious states, the electrodynamics of the cortex are poised near a critical point or phase transition and that this near-critical behavior supports the vast flow of information through cortical networks during conscious states. Here, we empirically identify a mathematically specific critical point near which waking cortical oscillatory dynamics operate, which is known as the edge-of-chaos critical point, or the boundary between stability and chaos. We do so by applying the recently developed modified 0-1 chaos test to electrocorticography (ECoG) and magnetoencephalography (MEG) recordings from the cortices of humans and macaques across normal waking, generalized seizure, anesthesia, and psychedelic states. Our evidence suggests that cortical information processing is disrupted during unconscious states because of a transition of low-frequency cortical electric oscillations away from this critical point; conversely, we show that psychedelics may increase the information richness of cortical activity by tuning low-frequency cortical oscillations closer to this critical point. Finally, we analyze clinical electroencephalography (EEG) recordings from patients with disorders of consciousness (DOC) and show that assessing the proximity of slow cortical oscillatory electrodynamics to the edge-of-chaos critical point may be useful as an index of consciousness in the clinical setting.

Neural Differentiation of Human Dental Mesenchymal Stem Cells Induced by ATRA and UDP-4: A Comparative Study.

Human mesenchymal stem cells (MSC) are multipotent stem cells, which are isolated from various sources. Currently, there is a worldwide interest for dental MSC to be used against neurodegenerative diseases, since they derive from the neural crest and express embryonic stem cell markers. This fact prompted us to explore their potential for neural trans-differentiation in culture. We employed all-trans-retinoic acid (ATRA) and 2-(3-ethylureido)-6-methylpyridine (UDP-4) to induce neural differentiation of human MSC from the dental apical papilla (SCAP). The SCAP were exposed to either agent separately and assessed for proliferation, viability, morphology, and gene expression of the following neural-specific markers: neuron-specific enolase (ENO2), neurofibromin 1 (NF1), choline acetyltransferase (CHAT), tyrosine hydroxylase (TH), and the vesicular GABA transporter (SLC32A1). They were also assessed for the expression of glial fibrillary acidic protein (GFAP) and neuronal nuclear antigen (NeuN) by immunofluorescence. ATRA or UDP-4 treatment inhibited the cell growth and promoted limited cell death, but to a different extent. The addition of the neuroprotective agent recombinant human erythropoietin-alpha (rhEPO-α) enhanced the UDP-4-inducing capacity for more than three weeks. ATRA or UDP-4 treatment significantly upregulated ENO2 and NF1 expression, indicating neuronal differentiation. Moreover, the ATRA treatment significantly induced the upregulation of the GABAergic-specific SLC32A1, while the UDP-4 treatment led to the significant upregulation of the adrenergic-specific TH. The UDP-4 treatment induced the expression of NeuN and GFAP after four and three weeks, respectively, while the ATRA-treatment did not. Our findings indicate that SCAP can be differentiated into neural-like cells after treatment with ATRA or UDP-4 by exhibiting a disparate pattern of differentiation. Therefore, UDP-4 is suggested here as a new potent neural-differentiation-inducing compound, which, when combined with rhEPO-α, could lay the foundation for robust stem-cell-based therapies of neurodegeneration.