Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) is most commonly used in a semi-quantitative manner to infer changes in brain activity. Despite the basis of the ...image contrast lying in the cerebral venous blood oxygenation level, quantification of absolute cerebral metabolic rate of oxygen consumption (CMRO2) has only recently been demonstrated. Here we examine two approaches to the calibration of fMRI signal to measure absolute CMRO2 using hypercapnic and hyperoxic respiratory challenges. The first approach is to apply hypercapnia and hyperoxia separately but interleaved in time and the second is a combined approach in which we apply hyperoxic challenges simultaneously with different levels of hypercapnia. Eleven healthy volunteers were studied at 3T using a dual gradient-echo spiral readout pulsed arterial spin labelling (ASL) imaging sequence. Respiratory challenges were conducted using an automated system of dynamic end-tidal forcing. A generalised BOLD signal model was applied, within a Bayesian estimation framework, that aims to explain the effects of modulation of CBF and arterial oxygen content to estimate venous deoxyhaemoglobin concentration (dHb0). Using CBF measurements combined with the estimated oxygen extraction fraction (OEF), absolute CMRO2 was calculated. The interleaved approach to hypercapnia and hyperoxia, as well as yielding estimates of CMRO2 and OEF demonstrated a significant increase in regional CBF, venous oxygen saturation (SvO2) (a decrease in OEF) and absolute CMRO2 in visual cortex in response to a continuous (20min) visual task, demonstrating the potential for the method in measuring long term changes in CMRO2. The combined approach to oxygen and carbon dioxide modulation, as well as taking less time to acquire data, yielded whole brain grey matter estimates of CMRO2 and OEF of 184±45μmol/100g/min and 0.42±0.12 respectively, along with additional estimates of the vascular parameters α=0.33±0.06, the exponent relating relative increases in CBF to CBV, and β=1.35±0.13, the exponent relating deoxyhaemoglobin concentration to the relaxation rate R2*. Maps of cerebrovascular and cerebral metabolic parameters were also calculated. We show that combined modulation of oxygen and carbon dioxide can offer an experimentally more efficient approach to estimating OEF and absolute CMRO2 along with the additional vascular parameters that form an important part of the commonly used calibrated fMRI signal model.
•We used hypercapnia and hyperoxia to measure OEF and absolute CMRO2.•Graded hypercapnia combined with hyperoxia gave values closest to PET studies.•This combined approach also yielded additional cerebrovascular constants (a and b).•We demonstrate a task-induced increase in absolute CMRO2 and decrease in OEF.•MRI measurement of CMRO2 has the potential to track changes in brain state.
Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary ...neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.
A new high-resolution Geophysical Fluid Dynamics Laboratory (GFDL) coupled model the High-Resolution Forecast-Oriented Low Ocean Resolution (FLOR) model (HiFLOR) has been developed and used to ...investigate potential skill in simulation and prediction of tropical cyclone (TC) activity. HiFLOR comprises high-resolution (∼25-km mesh) atmosphere and land components and a more moderate-resolution (∼100-km mesh) sea ice and ocean component. HiFLOR was developed from FLOR by decreasing the horizontal grid spacing of the atmospheric component from 50 to 25 km, while leaving most of the subgrid-scale physical parameterizations unchanged. Compared with FLOR, HiFLOR yields a more realistic simulation of the structure, global distribution, and seasonal and interannual variations of TCs, as well as a comparable simulation of storm-induced cold wakes and TC-genesis modulation induced by the Madden–Julian oscillation (MJO). Moreover, HiFLOR is able to simulate and predict extremely intense TCs (Saffir–Simpson hurricane categories 4 and 5) and their interannual variations, which represents the first time a global coupled model has been able to simulate such extremely intense TCs in a multicentury simulation, sea surface temperature restoring simulations, and retrospective seasonal predictions.
Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here ...we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.
The study of interaction effects is critical for creating, extending, and bounding theory in organizational research. Integrating and extending prior work, we present a taxonomy of two-way ...interaction effects that can guide organizational scholars toward clearer, more precise ways of developing theory, advancing hypotheses, and interpreting results. Specifically, we identify three primary interaction types, including strengthening, weakening, and reversing effects. In addition, we explore subcategories within these interaction types. Our review of articles published in leading management and applied psychology journals from 2009 to 2013 supports the generalizability of this framework. We offer specific recommendations for using this taxonomy to deliver more precise development, testing, and interpretation of interaction hypotheses.
We investigated the effects of updating age-specific social contact matrices to match evolving demography on vaccine impact estimates. We used a dynamic transmission model of tuberculosis in India as ...a case study. We modelled four incremental methods to update contact matrices over time, where each method incorporated its predecessor: fixed contact matrix (M0), preserved contact reciprocity (M1), preserved contact assortativity (M2), and preserved average contacts per individual (M3). We updated the contact matrices of a deterministic compartmental model of tuberculosis transmission, calibrated to epidemiologic data between 2000 and 2019 derived from India. We additionally calibrated the M0, M2, and M3 models to the 2050 TB incidence rate projected by the calibrated M1 model. We stratified age into three groups, children (<15y), adults (≥15y, <65y), and the elderly (≥65y), using World Population Prospects demographic data, between which we applied POLYMOD-derived social contact matrices. We simulated an M72-AS01E-like tuberculosis vaccine delivered from 2027 and estimated the per cent TB incidence rate reduction (IRR) in 2050 under each update method. We found that vaccine impact estimates in all age groups remained relatively stable between the M0-M3 models, irrespective of vaccine-targeting by age group. The maximum difference in impact, observed following adult-targeted vaccination, was 7% in the elderly, in whom we observed IRRs of 19% (uncertainty range 13-32), 20% (UR 13-31), 22% (UR 14-37), and 26% (UR 18-38) following M0, M1, M2 and M3 updates, respectively. We found that model-based TB vaccine impact estimates were relatively insensitive to demography-matched contact matrix updates in an India-like demographic and epidemiologic scenario. Current model-based TB vaccine impact estimates may be reasonably robust to the lack of contact matrix updates, but further research is needed to confirm and generalise this finding.
More effective tuberculosis vaccines are needed to help reach World Health Organization tuberculosis elimination goals. Insufficient evidence exists on the potential impact of future tuberculosis ...vaccines with varying characteristics and in different epidemiological settings. To inform vaccine development decision making, we modeled the impact of hypothetical tuberculosis vaccines in three high-burden countries. We calibrated
(
) transmission models to age-stratified demographic and epidemiological data from China, South Africa, and India. We varied vaccine efficacy to prevent infection or disease, effective in persons
uninfected or infected, and duration of protection. We modeled routine early-adolescent vaccination and 10-yearly mass campaigns from 2025. We estimated median percentage population-level tuberculosis incidence rate reduction (IRR) in 2050 compared to a no new vaccine scenario. In all settings, results suggested vaccines preventing disease in
-infected populations would have greatest impact by 2050 (10-year, 70% efficacy against disease, IRR 51%, 52%, and 54% in China, South Africa, and India, respectively). Vaccines preventing reinfection delivered lower potential impact (IRR 1, 12, and 17%). Intermediate impact was predicted for vaccines effective only in uninfected populations, if preventing infection (IRR 21, 37, and 50%) or disease (IRR 19, 36, and 51%), with greater impact in higher-transmission settings. Tuberculosis vaccines have the potential to deliver substantial population-level impact. For prioritizing impact by 2050, vaccine development should focus on preventing disease in
-infected populations. Preventing infection or disease in uninfected populations may be useful in higher transmission settings. As vaccine impact depended on epidemiology, different development strategies may be required.
India is located at a critical geographic crossroads for understanding the dispersal of Homo sapiens out of Africa and into Asia and Oceania. Here we report evidence for long-term human occupation, ...spanning the last ~80 thousand years, at the site of Dhaba in the Middle Son River Valley of Central India. An unchanging stone tool industry is found at Dhaba spanning the Toba eruption of ~74 ka (i.e., the Youngest Toba Tuff, YTT) bracketed between ages of 79.6 ± 3.2 and 65.2 ± 3.1 ka, with the introduction of microlithic technology ~48 ka. The lithic industry from Dhaba strongly resembles stone tool assemblages from the African Middle Stone Age (MSA) and Arabia, and the earliest artefacts from Australia, suggesting that it is likely the product of Homo sapiens as they dispersed eastward out of Africa.
APOBEC3B, an anti-viral cytidine deaminase which induces DNA mutations, has been implicated as a mediator of cancer evolution and therapeutic resistance. Mutational plasticity also drives generation ...of neoepitopes, which prime anti-tumor T cells. Here, we show that overexpression of APOBEC3B in tumors increases resistance to chemotherapy, but simultaneously heightens sensitivity to immune checkpoint blockade in a murine model of melanoma. However, in the vaccine setting, APOBEC3B-mediated mutations reproducibly generate heteroclitic neoepitopes in vaccine cells which activate de novo T cell responses. These cross react against parental, unmodified tumors and lead to a high rate of cures in both subcutaneous and intra-cranial tumor models. Heteroclitic Epitope Activated Therapy (HEAT) dispenses with the need to identify patient specific neoepitopes and tumor reactive T cells ex vivo. Thus, actively driving a high mutational load in tumor cell vaccines increases their immunogenicity to drive anti-tumor therapy in combination with immune checkpoint blockade.
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