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The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), and 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 8-92 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 60 s, 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., Competing Interests: XS, QS, KF, BO, XJ, BG, MH, EG, PK, EH, IP, MB, HK, SC, KJ, DW No competing interests declared, (© 2024, Shao et al.)

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-β (CSF sPDGFRβ, a marker of BBB breakdown) but have not demonstrated if this vascular impairment affects neuronal dysfunction. It's possible that increased levels of sPDGFRβ 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 sPDGFRβ 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 sPDGFRβ as a biomarker of BBB breakdown, we report that increased breakdown correlated with decreased functional connectivity in DMN areas, specifically the PCC, and while the hippocampus exhibited an interaction effect using CDR score, this was an exploratory analysis that we feel can lead to further research. Ultimately, we found that BBB breakdown, as measured by CSF sPDGFRβ, is associated with neural networks, and decreased functional connections., (© 2024. The Author(s).)

Introduction: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis., Methods: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale., Results: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach., Discussion: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification., Highlights: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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.

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., Competing Interests: Competing interests statement:The authors declare no competing interest.

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., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023 Massachusetts Institute of Technology.)

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., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Miklowitz receives research support from the National Institute of Mental Health, the Baszucki Brain Research Fund/Milken Foundation, Danny Alberts Foundation, Attias Family Foundation, Carl and Roberta Deutsch Foundation, and Max Gray Fund; and book royalties from Guilford Press and John Wiley and Sons. All other authors report no biomedical conflicts of interest. Tiffany C. Ho reports financial support was provided by National Institute of Mental Health. Saché M. Coury reports financial support was provided by National Institute of Mental Health. Steve Cole reports financial support was provided by National Institute of Mental Health. David J. Miklowitz reports financial support was provided by National Institute of Mental Health. Kate R. Kuhlman reports financial support was provided by National Institute of Mental Health. Yan Li reports financial support was provided by National Institute of Mental Health. Ioannis Pappas reports financial support was provided by National Institute of Mental Health. David J. Miklowitz reports a relationship with Guilford Press that includes: employment. David J. Miklowitz reports a relationship with John Wiley & Sons Inc that includes: employment. Author research support from the Baszucki Brain Research Fund/Milken Foundation - D.J.M. Author research support from the Danny Alberts Foundation - D.J.M. Author research support from the Attias Family Foundation - D.J.M. Author research support from the Cal and Roberta Deutsch Foundation - D.J.M. Author research support from the Max Gray Fund - D.J.M., (© 2023 The Authors.)

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., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., Competing Interests: The authors have no conflict of interest to report with regards to this study., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

In this contribution, we present a high-fidelity dynamic model of an industrial dividing wall column and the application of explicit model predictive control for its regulation. Our study involves the separation of methyl methacrylate from a quaternary mixture. The process includes a dividing wall column coupled with a decanter, which results in highly concentrated methyl methacrylate and water streams from the middle side draw of the column and the decanter, respectively. An equation-oriented mathematical model of the process is developed and presented in detail, where non-ideal thermodynamic calculations are adopted to describe the complex nature of the component interactions. The operability of the process is enhanced by the synthesis and application of an explicit model predictive controller, which is used to track the purity specifications of the product. Our results demonstrate that the proposed modeling and control approach can be utilized for the optimal online operation of the studied system., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Toga, Phatak, Pappas, Thompson, McHugh, Clement, Bauermeister, Maruyama and Gallacher.)

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., (© 2023. The Author(s).)

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., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author MI declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Purpose: The aim of the study is to optimize the performance of localized 1 H MRS sequences at 3T, using the entire spin system of N-acetyl aspartate (NAA) as an example of the large chemical shift spread of all the metabolites routinely detected in vivo, including the amide region. We specifically focus on the design of the suitable broadband excitation radiofrequency (RF) pulses to minimize chemical shift artifacts., Methods: The performance of the excitation and refocusing pulse shapes is evaluated with respect to NAA localization. Two new excitation RF pulses are developed to achieve optimized performance in the brain using single-voxel 1 H MRS at 3T. Numerical simulations and in vivo experiments are carried out to demonstrate the performance of the RF pulses., Results: New excitation RF pulses with the same B 1 requirements but larger excitation bandwidth (up to a factor of 2) are shown to significantly reduce localization artifacts. The large frequency spread of the entire NAA spin system necessitates the use of broadband excitation and refocusing pulses for MRS at 3T., Conclusion: To minimize chemical shift artifacts of metabolic compounds with spins in the amide area (>5 ppm) at 3T it is important to use broadband excitation and refocusing pulses., (© 2021 International Society for Magnetic Resonance in Medicine.)

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., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

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.

Human brains interpret external stimuli based on internal representations. One untested hypothesis is that the default-mode network (DMN), widely considered responsible for internally oriented cognition, can decode external information. Here, we posit that the unique structural and functional fingerprint of the precuneus (PCu) supports a prominent role for the posterior part of the DMN in this process. By analyzing the imaging data of 100 participants performing two attention-demanding tasks, we found that the PCu is functionally divided into dorsal and ventral subdivisions. We then conducted a comprehensive examination of their connectivity profiles and found that at rest, both the ventral PCu (vPCu) and dorsal PCu (dPCu) are mainly connected with the DMN but also are differentially connected with internally oriented networks (IoN) and externally oriented networks (EoN). During tasks, the double associations between the v/dPCu and the IoN/EoN are correlated with task performance and can switch depending on cognitive demand. Furthermore, dynamic causal modeling (DCM) revealed that the strength and direction of the effective connectivity (EC) between v/dPCu is modulated by task difficulty in a manner potentially dictated by the balance of internal versus external cognitive demands. Our study provides evidence that the posterior medial part of the DMN may drive interactions between large-scale networks, potentially allowing access to stored representations for moment-to-moment interpretation of an ever-changing environment. SIGNIFICANCE STATEMENT The default-mode network (DMN) is widely known for its association with internalized thinking processes, e.g., spontaneous thoughts, which is the most interesting but least understood component in human consciousness. The precuneus (PCu), a posteromedial DMN hub, is thought to play a role in this, but a mechanistic explanation has not yet been established. In this study we found that the associations between ventral PCu (vPCu)/dorsal PCu (dPCu) subdivisions and internally oriented network (IoN)/externally oriented network (EoN) are flexibly modulated by cognitive demand and correlate with task performance. We further propose that the recurrent causal connectivity between the ventral and dorsal PCu supports conscious processing by constantly interpreting external information based on an internal model, meanwhile updating the internal model with the incoming information., (Copyright © 2021 the authors.)

The cognitive effects of pharmacologically enhancing cortical dopamine (DA) tone are variable across healthy human adults. It has been postulated that individual differences in drug responses are linked to baseline cortical DA activity according to an inverted-U-shaped function. To better understand the effect of divergent starting points along this curve on DA drug responses, researchers have leveraged a common polymorphism (rs4680) in the gene encoding the enzyme catechol-O-methyltransferase (COMT) that gives rise to greater (Met allele) or lesser (Val allele) extracellular levels of cortical DA. Here we examined the extent to which changes in resting cortical perfusion following the administration of two mechanistically-distinct dopaminergic drugs vary by COMT genotype, and thereby track predictions of the inverted-U model. Using arterial spin labeling (ASL) and a double-blind, within-subject design, perfusion was measured in 75 healthy, genotyped participants once each after administration of tolcapone (a COMT inhibitor), bromocriptine (a DA D2/3 agonist), and placebo. COMT genotype and drug interacted such that COMT Val homozygotes exhibited increased prefusion in response to both drugs, whereas Met homozygotes did not. Additionally, tolcapone-related perfusion changes in the right inferior frontal gyrus correlated with altered performance on a task of executive function. No comparable effects were found for a genetic polymorphism (rs1800497) affecting striatal DA system function. Together, these results indicate that both the directionality and magnitude of drug-induced perfusion change provide meaningful information about individual differences in response to enhanced cortical DA tone., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2021. Published by Elsevier Inc.)

In MRI studies, spatial normalization is required to infer results at the group level. In the presence of a brain lesion, such as in stroke patients, the normalization process can be affected by tissue loss, spatial deformations, signal intensity changes, and other stroke sequelae that introduce confounds into the group analysis results. Previously, most neuroimaging studies with lesioned brains have used normalization methods optimized for intact brains, raising potential concerns about the accuracy of the resulting transformations and, in turn, their reported group level results. In this study, we demonstrate the benefits of creating an intermediate, cohort-specific template in conjunction with diffeomorphism-based methods to normalize structural MRI images in stroke patients. We show that including this cohort-specific template improves accuracy compared to standard methods for normalizing lesioned brains. Critically, this method reduces overall differences in normalization accuracy between stroke patients and healthy controls, and may improve the localization and connectivity of BOLD signal in functional neuroimaging data., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Industrial process systems need to be optimized, simultaneously satisfying financial, quality and safety criteria. To meet all those potentially conflicting optimization objectives, multiobjective optimization formulations can be used to derive optimal trade-off solutions. In this work, we present a framework that provides the exact Pareto front of multiobjective mixed-integer linear optimization problems through multiparametric programming. The original multiobjective optimization program is reformulated through the well-established ϵ -constraint scalarization method, in which the vector of scalarization parameters is treated as a right-hand side uncertainty for the multiparametric program. The algorithmic procedure then derives the optimal solution of the resulting multiparametric mixed-integer linear programming problem as an affine function of the ϵ parameters, which explicitly generates the Pareto front of the multiobjective problem. The solution of a numerical example is analytically presented to exhibit the steps of the approach, while its practicality is shown through a simultaneous process and product design problem case study. Finally, the computational performance is benchmarked with case studies of varying dimensionality with respect to the number of objective functions and decision variables.

Background: Propofol, a commonly used intravenous anaesthetic, binds to type A gamma aminobutyric acid (GABA) receptors in mammalian brain. Previous work on its anaesthetic action has characterised either the biochemistry underlying propofol binding or the associated changes in brain network dynamics during sedation. Despite these advances, no study has focused on understanding how propofol action at the cellular level results in changes in brain network connectivity., Methods: We used human whole-brain microarray data to generate distribution maps for genes that mark the primary GABAergic cortical interneurone subtypes (somatostatin, parvalbumin [PV], and 5-hydroxytryptamine 3A. Next, 25 healthy participants underwent propofol-induced sedation during resting state functional MRI scanning. We used partial least squares analysis to identify the brain regions in which connectivity patterns were most impacted by propofol sedation. We then correlated these multimodal cortical patterns to determine if a specific interneurone subtype was disproportionately expressed in brain regions in which connectivity patterns were altered during sedation., Results: Brain networks that were significantly altered by propofol sedation had a high density of PV-expressing GABAergic interneurones. Brain networks that anticorrelated during normal wakefulness, namely the default mode network and attentional and frontoparietal control networks, increased in correlation during sedation., Conclusions: PV-expressing interneurones are highly expressed in brain regions with altered connectivity profiles during propofol-induced sedation. This study also demonstrates the utility of leveraging multiple datasets to address multiscale neurobiological problems., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Investigating changes in brain function induced by mind-altering substances such as LSD is a powerful method for interrogating and understanding how mind interfaces with brain, by connecting novel psychological phenomena with their neurobiological correlates. LSD is known to increase measures of brain complexity, potentially reflecting a neurobiological correlate of the especially rich phenomenological content of psychedelic-induced experiences. Yet although the subjective stream of consciousness is a constant ebb and flow, no studies to date have investigated how LSD influences the dynamics of functional connectivity in the human brain. Focusing on the two fundamental network properties of integration and segregation, here we combined graph theory and dynamic functional connectivity from resting-state functional MRI to examine time-resolved effects of LSD on brain networks properties and subjective experiences. Our main finding is that the effects of LSD on brain function and subjective experience are non-uniform in time: LSD makes globally segregated sub-states of dynamic functional connectivity more complex, and weakens the relationship between functional and anatomical connectivity. On a regional level, LSD reduces functional connectivity of the anterior medial prefrontal cortex, specifically during states of high segregation. Time-specific effects were correlated with different aspects of subjective experiences; in particular, ego dissolution was predicted by increased small-world organisation during a state of high global integration. These results reveal a more nuanced, temporally-specific picture of altered brain connectivity and complexity under psychedelics than has previously been reported., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Measures of human brain functional connectivity acquired during the resting-state track critical aspects of behavior. Recently, fluctuations in resting-state functional connectivity patterns-typically averaged across in traditional analyses-have been considered for their potential neuroscientific relevance. There exists a lack of research on the differences between traditional "static" measures of functional connectivity and newly considered "time-varying" measures as they relate to human behavior. Using functional magnetic resonance imagining (fMRI) data collected at rest, and a battery of behavioral measures collected outside the scanner, we determined the degree to which each modality captures aspects of personality and cognitive ability. Measures of time-varying functional connectivity were derived by fitting a hidden Markov model. To determine behavioral relationships, static and time-varying connectivity measures were submitted separately to canonical correlation analysis. A single relationship between static functional connectivity and behavior existed, defined by measures of personality and stable behavioral features. However, two relationships were found when using time-varying measures. The first relationship was similar to the static case. The second relationship was unique, defined by measures reflecting trialwise behavioral variability. Our findings suggest that time-varying measures of functional connectivity are capable of capturing unique aspects of behavior to which static measures are insensitive., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2020 Massachusetts Institute of Technology.)

The pandemic COVID 19 has altered individuals' daily lives across the globe. It has led to preventive measures such as physical distancing to be imposed on individuals and led to terms such as 'lockdown,' 'emergency,' or curfew' to emerge in various countries. It has affected society, not only physically and financially, but in terms of emotional wellbeing as well. This distress in the human emotional quotient results from multiple factors such as financial implications, family member's behavior and support, country-specific lockdown protocols, media influence, or fear of the pandemic. For efficient pandemic management, there is a need to understand the emotional variations among individuals, as this will provide insights into public sentiment towards various government pandemic management policies. From our investigations, it was found that individuals have increasingly used different microblogging platforms such as Twitter to remain connected and express their feelings and concerns during the pandemic. However, research in the area of expressed emotional wellbeing during COVID 19 is still growing, which motivated this team to form the aim: To identify, explore and understand globally the emotions expressed during the earlier months of the pandemic COVID 19 by utilizing Deep Learning and Natural language Processing (NLP). For the data collection , over 2 million tweets during February-June 2020 were collected and analyzed using an advanced deep learning technique of Transfer Learning and Robustly Optimized BERT Pretraining Approach (RoBERTa). A Reddit-based standard Emotion Dataset by Crowdflower was utilized for transfer learning. Using RoBERTa and the collated Twitter dataset, a multi-class emotion classifier system was formed. With the implemented methodology, a tweet classification accuracy of 80.33% and an average MCC score of 0.78 was achieved, improving the existing AI-based emotion classification methods. This study explains the novel application of the Roberta model during the pandemic that provided insights into changing emotional wellbeing over time of various citizens worldwide. It also offers novelty for data mining and analytics during this challenging, pandemic era. These insights can be beneficial for formulating effective pandemic management strategies and devising a novel, predictive strategy for the emotional well-being of an entire country's citizens when facing future unexpected exogenous shocks., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.)

The construction and expansion of steam cracking plants and feedstock diversification have resulted in a significant demand for the numerical simulation and optimization of models to achieve molecular refining and intelligent manufacturing. However, the existing models cannot be widely applied in industrial practice because of the high computational expense, time-consumption, and data size requirements. In this paper, a high-performance optimization process, which integrates transfer learning and a heuristic algorithm, is proposed for the optimization of furnaces for various feedstocks. An effective transfer learning structure, based on motif feature of the reaction network, is designed and subsequent product distribution prediction program is compiled. Then a hybrid genetic algorithm and particle swarm optimization method is applied for the coil outlet temperature (COT) curve optimization using the derived prediction model, and the results are obtained for different pricing policies of products. The results are determined based on the weight coefficients of prices for different products, and could be further explained by the yield distribution pattern and reaction mechanism., Competing Interests: The authors declare no competing financial interest.

The human brain exhibits a rich functional repertoire in terms of complex functional connectivity patterns during rest and tasks. However, how this is developed upon a fixed structural anatomy remains poorly understood. Here we investigated the hypothesis that resting state functional connectivity and the manner in which it changes during tasks related to a set of underlying structural connections that promote optimal communication in the brain. We used a game-theoretic model to identify such optimal connections in the structural connectome of 50 healthy individuals and subsequently used the optimal structural connections to predict resting-state functional connectivity with high accuracy. In contrast, we found that nonoptimal connections accurately predicted functional connectivity during a working memory task. We further found that this balance between optimal and nonoptimal connections between brain regions was associated with a specific gene expression linked to neurotransmission. This multimodal evidence shows for the first time that structure-function relationships in the human brain are related to how brain networks navigate information along different white matter connections as well as the brain's underlying genetic profile., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

The brain is possibly the most complex system known to mankind, and its complexity has been called upon to explain the emergence of consciousness. However, complexity has been defined in many ways by multiple different fields: here, we investigate measures of algorithmic and process complexity in both the temporal and topological domains, testing them on functional MRI BOLD signal data obtained from individuals undergoing various levels of sedation with the anaesthetic agent propofol, replicating our results in two separate datasets. We demonstrate that the various measures are differently able to discriminate between levels of sedation, with temporal measures showing higher sensitivity. Further, we show that all measures are strongly related to a single underlying construct explaining most of the variance, as assessed by Principal Component Analysis, which we interpret as a measure of "overall complexity" of our data. This overall complexity was also able to discriminate between levels of sedation and serum concentrations of propofol, supporting the hypothesis that consciousness is related to complexity - independent of how the latter is measured.

Olive oil mill wastewater (OMW) is a significant pollutant in the Mediterranean region. In the present contribution, we showed clearly that microorganisms (microalgae and OMW-microflora) activated the biodegradation of OMW-phenolics and produced a high yield of hydrogen (H 2 ). In a closed incubation system, the appropriate adjustment of OMW-pH leads to the establishment of anoxic conditions through the oxygen consumption of microorganisms during the first incubation day. The biodegradation procedure of OMW-phenolics needs oxygen. Therefore, after the establishment of anoxic conditions, the biodegradation stopped and the activation of hydrogenases started, leading to a continuous high yield of bio-hydrogen production. If the cultivation system re-opened (oxygen enrichment), the OMW-phenolic biodegradation (oxygen dependent process) started again and therefore the detoxified OMW could be used for further biotechnological applications (production of biodiesel, bioalcohols, organic fertilizers, etc.). Apart from the environmental compatibility of the method and the sustainability of such a combinational application (OMW detoxification and high yield of hydrogen production) in the context of a green biotechnology approach, the cost/profit ratio appears to be particularly tempting and guarantees its widespread use in the near future. The present contribution proposes a solution to a major environmental problem by upgrading its solution to a high-value product., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Functional brain connectivity studies can provide important information about changes in brain-state dynamics during general anesthesia. In adults, γ-aminobutyric acid-mediated agents disrupt integration of information from local to the whole-brain scale. Beginning around 3 to 4 months postnatal age, γ-aminobutyric acid-mediated anesthetics such as sevoflurane generate α-electroencephalography oscillations. In previous studies of sevoflurane-anesthetized infants 0 to 3.9 months of age, α-oscillations were absent, and power spectra did not distinguish between anesthetized and emergence from anesthesia conditions. Few studies detailing functional connectivity during general anesthesia in infants exist. This study's aim was to identify changes in functional connectivity of the infant brain during anesthesia., Methods: A retrospective cohort study was performed using multichannel electroencephalograph recordings of 20 infants aged 0 to 3.9 months old who underwent sevoflurane anesthesia for elective surgery. Whole-brain functional connectivity was evaluated during maintenance of a surgical state of anesthesia and during emergence from anesthesia. Functional connectivity was represented as networks, and network efficiency indices (including complexity and modularity) were computed at the sensor and source levels., Results: Sevoflurane decreased functional connectivity at the δ-frequency (1 to 4 Hz) in infants 0 to 3.9 months old when comparing anesthesia with emergence. At the sensor level, complexity decreased during anesthesia, showing less whole-brain integration with prominent alterations in the connectivity of frontal and parietal sensors (median difference, 0.0293; 95% CI, -0.0016 to 0.0397). At the source level, similar results were observed (median difference, 0.0201; 95% CI, -0.0025 to 0.0482) with prominent alterations in the connectivity between default-mode and frontoparietal regions. Anesthesia resulted in fragmented modules as modularity increased at the sensor (median difference, 0.0562; 95% CI, 0.0048 to 0.1298) and source (median difference, 0.0548; 95% CI, -0.0040 to 0.1074) levels., Conclusions: Sevoflurane is associated with decreased capacity for efficient information transfer in the infant brain. Such findings strengthen the hypothesis that conscious processing relies on an efficient system of integrated information transfer across the whole brain.

Prominent theories of consciousness emphasise different aspects of neurobiology, such as the integration and diversity of information processing within the brain. Here, we combine graph theory and dynamic functional connectivity to compare resting-state functional MRI data from awake volunteers, propofol-anaesthetised volunteers, and patients with disorders of consciousness, in order to identify consciousness-specific patterns of brain function. We demonstrate that cortical networks are especially affected by loss of consciousness during temporal states of high integration, exhibiting reduced functional diversity and compromised informational capacity, whereas thalamo-cortical functional disconnections emerge during states of higher segregation. Spatially, posterior regions of the brain's default mode network exhibit reductions in both functional diversity and integration with the rest of the brain during unconsciousness. These results show that human consciousness relies on spatio-temporal interactions between brain integration and functional diversity, whose breakdown may represent a generalisable biomarker of loss of consciousness, with potential relevance for clinical practice.

The mechanism of C(sp 2 )-H borylation of fluorinated arenes with B 2 Pin 2 (Pin = pinacolato) catalyzed by bis(phosphino)pyridine ( iPr PNP) cobalt complexes was studied to understand the origins of the uniquely high ortho -to-fluorine regioselectivity observed in these reactions. Variable time normalization analysis (VTNA) of reaction time courses and deuterium kinetic isotope effect measurements established a kinetic regime wherein C(sp 2 )-H oxidative addition is fast and reversible. Monitoring the reaction by in situ NMR spectroscopy revealed the intermediacy of a cobalt(I)-aryl complex that was generated with the same high ortho -to-fluorine regioselectivity associated with the overall catalytic transformation. Deuterium labeling experiments and stoichiometric studies established C(sp 2 )-H oxidative addition of the fluorinated arene as the selectivity-determining step of the reaction. This step favors the formation of ortho -fluoroaryl cobalt intermediates due to the ortho fluorine effect, a phenomenon whereby ortho fluorine substituents stabilize transition metal-carbon bonds. Computational studies provided evidence that the cobalt-carbon bonds of the relevant intermediates in ( iPr PNP)Co-catalyzed borylation are strengthened with increasing ortho fluorine substitution. The atypical kinetic regime involving fast and reversible C(sp 2 )-H oxidative addition in combination with the thermodynamic preference for forming cobalt-aryl bonds adjacent to fluorinated sites are the origin of the high regioselectivity in the catalytic borylation reaction.

Vitamin A (VA) is an essential nutrient needed in small amounts by humans and supports a wide range of biological actions. Retinol, the most common and most biologically active form of VA has also been found to inhibit peroxidation processes in membranes and it has been widely used as an ingredient with pharmaceutical and nutritional applications. VA is a lipophilic molecule, sensitive to air, oxidizing agents, ultraviolet light and low pH levels. For these reasons, it is necessary for VA to be protected against oxidation. Another disadvantage in the application of VA is its low solubility in aqueous media. Both issues (sensitivity and solubility) can be solved by employing encapsulation techniques. Liposomes can efficiently encapsulate lipid-soluble materials, such as VA. The encapsulated materials are protected from environmental and chemical changes. A new liposome/β-lactoglobulin formulation has been developed as a stable delivery system for VA. The aim of this study was the encapsulation of VA into β-lactoglobulin-liposome complexes, recently developed in our laboratory. The in vivo bioavailability characterization of VA was tested after administration in laboratory animals (mice). In this report, we demonstrate that VA could be efficiently entrapped and delivered in a phospholipid-sterol-protein membrane resembling system, a newly synthesized promising carrier. Based on this finding, the phospholipid-sterol-protein membrane resembling system may be one of the promising approaches to enhance VA absorption and to overcome the formulation difficulties associated with lipophilic means. The carrier system described here has huge potential in food fortification applications to treat VA deficiency.

Background: Stannous fluoride (SnF 2 ) is a compound present in many commercially available dentifrices; however, oxidative decomposition negatively impacts its efficacy. Stannous oxidation is often mitigated through the addition of complexing agents or sources of sacrificial stannous compounds. The authors have found that the addition of zinc phosphate significantly improved stannous stability more effectively than other stabilization methods. The authors evaluated the chemical speciation of stannous compounds within a variety of formulations using x-ray absorption near edge spectroscopy (XANES), a technique never used before in this manner. These data were compared and correlated with several antimicrobial experiments., Methods: XANES data of various commercially available compounds and Colgate Total SF were performed and analyzed against a library of reference compounds to determine the tin chemical speciation. The antibacterial assays used were salivary adenosine triphosphate, short-interval kill test, plaque glycolysis, and anaerobic biofilm models., Results: XANES spectra showed a diverse distribution of tin species and varying degrees of SnF 2 oxidation. In vitro antimicrobial assessment indicated significant differences in performance, which may be correlated to the differences in tin speciation and oxidation state., Conclusions: Driven by the excipient ingredients, SnF 2 dentifrices contain a distribution of tin species in either the SnF 2 or Sn(IV) oxidation state. The addition of zinc phosphate provided significant robustness against oxidation, which directly translated to greater efficacy against bacteria., Practical Implications: The choice of inactive ingredients in a dentifrice with active SnF 2 can dramatically impact product stability., (Copyright © 2019 American Dental Association. Published by Elsevier Inc. All rights reserved.)

The precise mechanism of anaesthetic action on a neural level remains unclear. Recent approaches suggest that anaesthetics attenuate the complexity of interactions (connectivity) however evidence remains insufficient. We used tools from network and information theory to show that, during propofol-induced sedation, a collection of brain regions displayed decreased complexity in their connectivity patterns, especially so if they were sparsely connected. Strikingly, we found that, despite their low connectivity strengths, these regions exhibited an inordinate role in network integration. Their location and connectivity complexity delineated a specific pattern of sparse interactions mainly involving default mode regions while their connectivity complexity during the awake state also correlated with reaction times during sedation signifying its importance as a reliable indicator of the effects of sedation on individuals. Contrary to established views suggesting sedation affects only richly connected brain regions, we propose that suppressed complexity of sparsely connected regions should be considered a critical feature of any candidate mechanistic description for loss of consciousness., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The hydrogenolysis of titanium-nitrogen bonds in a series of bis(cyclopentadienyl) titanium amides, hydrazides and imides by proton coupled electron transfer (PCET) is described. Twelve different N-H bond dissociation free energies (BDFEs) among the various nitrogen-containing ligands were measured or calculated, and effects of metal oxidation state and N-ligand substituent were determined. Two metal hydride complexes, (η 5 -C 5 Me 5 )(py-Ph)Rh-H (py-Ph = 2-pyridylphenyl, [Rh]-H) and (η 5 -C 5 R 5 )(CO) 3 Cr-H ([Cr] R -H, R= H, Me) were evaluated for formal H atom transfer reactivity and were selected due to their relatively weak M-H bond strengths yet ability to activate and cleave molecular hydrogen. Despite comparable M-H BDFEs, disparate reactivity between the two compounds was observed and was traced to the vastly different acidities of the M-H bonds and overall redox potentials of the molecules. With [Rh]-H, catalytic syntheses of ammonia, silylamine and N,N-dimethylhydrazine have been accomplished from the corresponding titanium(IV) complex using H 2 as the stoichiometric H atom source. The data presented in this study provides the thermochemical foundation for the synthesis of NH 3 by proton coupled electron transfer at a well-defined transition metal center.

A comprehensive study into the mechanism of bis(phosphino)pyridine (PNP) cobalt-catalyzed C-H borylation of 2,6-lutidine using B2Pin2 (Pin = pinacolate) has been conducted. The experimentally observed rate law, deuterium kinetic isotope effects, and identification of the catalyst resting state support turnover limiting C-H activation from a fully characterized cobalt(I) boryl intermediate. Monitoring the catalytic reaction as a function of time revealed that borylation of the 4-position of the pincer in the cobalt catalyst was faster than arene borylation. Cyclic voltammetry established the electron withdrawing influence of 4-BPin, which slows the rate of C-H oxidative addition and hence overall catalytic turnover. This mechanistic insight inspired the next generation of 4-substituted PNP cobalt catalysts with electron donating and sterically blocking methyl and pyrrolidinyl substituents that exhibited increased activity for the C-H borylation of unactivated arenes. The rationally designed catalysts promote effective turnover with stoichiometric quantities of arene substrate and B2Pin2. Kinetic studies on the improved catalyst, 4-(H)2BPin, established a change in turnover limiting step from C-H oxidative addition to C-B reductive elimination. The iridium congener of the optimized cobalt catalyst, 6-(H)2BPin, was prepared and crystallographically characterized and proved inactive for C-H borylation, a result of the high kinetic barrier for reductive elimination from octahedral Ir(III) complexes.

Synthesis of coordinatively unsaturated Cp*Co(IPr) (2), is accomplished by addition of free N-heterocyclic carbene IPr to [(Cp*Co)2-μ-(η(4):η(4)-toluene)] (1). Stoichiometric reactivity is consistent with a 16 electron species, as 2 undergoes ligand addition/NHC displacement and reversible reaction with dihydrogen. Cp*Co(IPr) represents an elusive example of a stable Cp*CoL fragment.

Cobalt dialkyl and bis(carboxylate) complexes bearing α-diimine ligands have been synthesized and demonstrated as active for the C(sp(3))-H borylation of a range of substituted alkyl arenes using B2Pin2 (Pin = pinacolate) as the boron source. At longer reaction times, rare examples of polyborylation were observed, and in the case of toluene, all three benzylic C-H positions were functionalized. Coupling benzylic C-H activation with alkyl isomerization enabled a base-metal-catalyzed method for the borylation of remote, unactivated C(sp(3))-H bonds.

Functional Magnetic Resonance (fMRI) data can be used to depict functional connectivity of the brain. Standard techniques have been developed to construct brain networks from this data; typically nodes are considered as voxels or sets of voxels with weighted edges between them representing measures of correlation. Identifying cognitive states based on fMRI data is connected with recording voxel activity over a certain time interval. Using this information, network and machine learning techniques can be applied to discriminate the cognitive states of the subjects by exploring different features of data. In this work we wish to describe and understand the organization of brain connectivity networks under cognitive tasks. In particular, we use a regularity partitioning algorithm that finds clusters of vertices such that they all behave with each other almost like random bipartite graphs. Based on the random approximation of the graph, we calculate a lower bound on the number of triangles as well as the expectation of the distribution of the edges in each subject and state. We investigate the results by comparing them to the state of the art algorithms for exploring connectivity and we argue that during epochs that the subject is exposed to stimulus, the inspected part of the brain is organized in an efficient way that enables enhanced functionality.

The effects of modification of the in vitro embryo culture media (IVC) with the addition of urokinase-type plasminogen activator (u-PA) on the yield and/or quality of bovine embryos were examined in two experiments. In Experiment 1, denuded embryos were cultured in semi-defined synthetic oviductal fluid (SOF) for seven days, while in Experiment 2 embryos were co-cultured with cumulus cell monolayer in a serum-containing SOF medium. Plasminogen activator activity (PAA) and plasminogen activator inhibition (PAI) were determined in all spent IVC media. At the activity used (5 IU/ml), u-PA had no effect either on in vitro embryo production rates or on embryo quality as revealed by gene expression analysis of 10 important mRNA transcripts related to apoptosis, oxidation, implantation and metabolism. PAA and PAI analysis indicated the need for wellbalanced plasminogen activators and inhibitors as a culture environment for embryo development. However, more research is needed to unveil the mechanism by which u-PA is involved in in vitro embryo production systems.

A bis(imino)pyridine cobalt-catalyzed hydroboration of terminal alkynes with HBPin (Pin = pinacolate) with high yield and (Z)-selectivity for synthetically valuable vinylboronate esters is described. Deuterium labeling studies, stoichiometric experiments, and isolation of catalytically relevant intermediates support a mechanism involving selective insertion of an alkynylboronate ester into a Co-H bond, a pathway distinct from known precious metal catalysts where metal vinylidene intermediates have been proposed to account for the observed (Z) selectivity. The identity of the imine substituents dictates the relative rates of activation of the cobalt precatalyst with HBPin or the terminal alkyne and, as a consequence, is responsible for the stereochemical outcome of the catalytic reaction.

The catalytic hydrogenolysis of the titanium-amide bond in (η(5)-C5Me4SiMe3)2Ti(Cl)NH2 to yield free ammonia is described. The rhodium hydride, (η(5)-C5Me5)(py-Ph)RhH (py-Ph = 2-phenylpyridine), serves as the catalyst and promotes N-H bond formation via hydrogen atom transfer. The N-H bond dissociation free energies of ammonia ligands have also been determined for titanocene and zirconocene complexes and reveal a stark dependence on metal identity and oxidation state. In all cases, the N-H BDFEs of coordinated NH3 decreases by >40 kcal/mol from the value in the free gas phase molecule.

The interactions between commercial antiperspirant (AP) salts [aluminum chlorohydrate (ACH), activated ACH, aluminum sesquichlorohydrate (ASCH), zirconium aluminum glycine (ZAG), activated ZAG), pure aluminum polyoxocations (Al13-mer, Al30-mer), and the zirconium(IV)-glycine complex Zr6 (O)4 (OH)4 (H2O)8 (Gly)8]12+(-) (CP-2 or ZG) with Bovine serum albumin (BSA) were studied using zeta potential and turbidity measurements. The maximal turbidity, which revealed the optimal interactions between protein and metal salts, for all protein-metal salt samples was observed at the isoelectric point (IEP), where the zeta potential of the solution was zero. Efficacy of AP salts was determined via three parameters: the amount of salt required to flocculate BSA to reach IEP, the turbidity of solution at the IEP, and the pH range over which the turbidity of the solution remains sufficiently high. By comparing active salt performance from this work to traditional prescreening methods, this methodology was able to provide a consistent efficacy assessment for metal actives in APs or in water treatment.

Dietary supplementation with a multi-strain probiotic containing Bacillus subtilis, Enterococcus faecium, Pediococcus acidilactici and Lactobacillus reuteri has been examined for its effects on growth performance, intestinal microbiota, non-specific immune response and antioxidant status of rainbow trout. Three groups of sub-adult trout were stocked into experimental tanks. A commercial diet was used as control, while the other two groups received diets supplemented with the multi-strain probiotic at levels of 1 and 5 g kg(-1) diet. The fish were fed to apparent satiation three times daily for 8 weeks. Dietary probiotic at 1 g kg(-1) diet improved (P < 0.05) growth and feed efficiency compared to control diet. Lactic acid bacteria loads were higher in probiotic fed fish at both inclusion levels compared to control; however, Enterobacteriaceae, Coliforms and Aeromonas spp. were similar between groups. Dietary probiotics decreased (P < 0.05) malondialdehyde formation on day 0 compared to control fish but not on day 5 of storage. Probiotics also increased (P < 0.05) the activity of glutathione-based enzymes. Serum lysozyme levels were similar among dietary treatments. Probiotic supplementation at 1 g kg(-1) diet reduced serum nitric oxide levels compared to control. In conclusion, dietary probiotics at the level of 1 g kg(-1) of diet exerted both a growth promoting and antioxidant protective activity.

Plasminogen activators/Plasmin system plays pivotal role in regulating reproductive functions of mammals. Here, we examined the effects of modification of in vitro fertilization medium (IVF medium) with the addition of tissue-type plasminogen activator (t-PA), on bovine embryo development and quality, assessed by quantification of expression of various genes related to metabolism, oxidation, implantation and apoptosis. In addition, plasminogen activator activity (PAA) and plasminogen activator inhibition (PAI) were measured in the spent media. After conventional IVM, 2016 cumulus-oocyte complexes (COCs) were divided into four groups with modified composition of the IVF medium containing t-PA and/or its inhibitor epsilon-aminocaproic acid (control, t-PA, t-PA+ε-ACA, ε-ACA). Presumptive zygotes were cultured for 8 days in synthetic oviductal fluid (SOF) medium; gene expression studies were carried out on morulae and blastocysts. t-PA alone significantly suppressed cleavage and blastocyst formation rates, but this effect was neutralized by the addition of ε-ACA. PAA in the treated group was significantly reduced by ε-ACA, but without total elimination. Significant differences were detected in the expression of genes related to apoptosis and/or cell cycle arrest (BAX, BCL2L1, KAT2B) between embryos produced in t-PA-modified media and controls, giving an overall notion that the inferior developmental competence of treated embryos may be attributed to apoptotic phenomena induced by t-PA. In conclusion, it appears that excessive t-PA content in the IVF media, suppresses blastocyst formation rate, possibly due to induction of apoptotic phenomena., (© 2014 Blackwell Verlag GmbH.)