Extracellular electron uptake (EEU) is the ability of microbes to take up electrons from solid-phase conductive substances such as metal oxides. EEU is performed by prevalent phototrophic bacterial ...genera, but the electron transfer pathways and the physiological electron sinks are poorly understood. Here we show that electrons enter the photosynthetic electron transport chain during EEU in the phototrophic bacterium Rhodopseudomonas palustris TIE-1. Cathodic electron flow is also correlated with a highly reducing intracellular redox environment. We show that reducing equivalents are used for carbon dioxide (CO
) fixation, which is the primary electron sink. Deletion of the genes encoding ruBisCO (the CO
-fixing enzyme of the Calvin-Benson-Bassham cycle) leads to a 90% reduction in EEU. This work shows that phototrophs can directly use solid-phase conductive substances for electron transfer, energy transduction, and CO
fixation.
Silent cerebral infarcts (SCIs) are associated with cognitive impairment in sickle cell anemia (SCA). SCI risk factors include low hemoglobin and elevated systolic blood pressure; however, mechanisms ...underlying their development are unclear. Using the largest prospective study evaluating SCIs in pediatric SCA, we identified brain regions with increased SCI density. We tested the hypothesis that infarct density is greatest within regions in which cerebral blood flow is lowest, further restricting cerebral oxygen delivery in the setting of chronic anemia. Neuroradiology and neurology committees reached a consensus of SCIs in 286 children in the Silent Infarct Transfusion (SIT) Trial. Each infarct was outlined and coregistered to a brain atlas to create an infarct density map. To evaluate cerebral blood flow as a function of infarct density, pseudocontinuous arterial spin labeling was performed in an independent pediatric SCA cohort. Blood flow maps were aligned to the SIT Trial infarct density map. Mean blood flow within low, moderate, and high infarct density regions from the SIT Trial were compared. Logistic regression evaluated clinical and imaging predictors of overt stroke at 3-year follow-up. The SIT Trial infarct density map revealed increased SCI density in the deep white matter of the frontal and parietal lobes. A relatively small region, measuring 5.6% of brain volume, encompassed SCIs from 90% of children. Cerebral blood flow was lowest in the region of highest infarct density (P < .001). Baseline infarct volume and reticulocyte count predicted overt stroke. In pediatric SCA, SCIs are symmetrically located in the deep white matter where minimum cerebral blood flow occurs.
•The SCI density map revealed key SCI locations in the deep white matter of the frontal and parietal lobes.•Peak SCI density occurs in the region of nadir cerebral blood flow.
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To determine mechanisms underlying regional vulnerability to infarction in sickle cell disease (SCD) by measuring voxel-wise cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral ...metabolic rate of oxygen utilization (CMRO
) in children with SCD.
Participants underwent brain MRIs to measure voxel-based CBF, OEF, and CMRO
. An infarct heat map was created from an independent pediatric SCD cohort with silent infarcts and compared to prospectively obtained OEF maps.
Fifty-six participants, 36 children with SCD and 20 controls, completed the study evaluation. Whole-brain CBF (99.2 vs 66.3 mL/100 g/min,
< 0.001), OEF (42.7% vs 28.8%,
< 0.001), and CMRO
(3.7 vs 2.5 mL/100 g/min,
< 0.001) were higher in the SCD cohort compared to controls. A region of peak OEF was identified in the deep white matter in the SCD cohort, delineated by a ratio map of average SCD to control OEF voxels. CMRO
in this region, which encompassed the CBF nadir, was low relative to all white matter (
< 0.001). Furthermore, this peak OEF region colocalized with regions of greatest infarct density derived from an independent SCD cohort.
Elevated OEF in the deep white matter identifies a signature of metabolically stressed brain tissue at increased stroke risk in pediatric patients with SCD. We propose that border zone physiology, exacerbated by chronic anemic hypoxia, explains the high risk in this region.
Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated ...oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs; OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared with patients not receiving disease-modifying therapy, we prospectively obtained brain magnetic resonance imaging scans with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole-brain CBF among the 3 cohorts (P = .148). However, whole-brain OEF was significantly different (P < .001): participants without disease-modifying therapy had the highest OEF (median 42.9% interquartile range (IQR) 39.1%-49.1%), followed by HU treatment (median 40.7% IQR 34.9%-43.6%), whereas CTT treatment had the lowest values (median 35.3% IQR 32.2%-38.9%). Moreover, the percentage of white matter at highest risk for ischemia, defined by OEF greater than 40% and 42.5%, was lower in the HU cohort compared with the untreated cohort (P = .025 and P = .034 respectively), but higher compared with the CTT cohort (P = .018 and P = .029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT.
•Cerebral metabolic stress is reduced in SCA patients receiving HU compared with untreated patients, but remains higher than patients receiving CTT.•HU reduces the volume of tissue with maximal metabolic stress in the internal border zone, a region at high risk for stroke.
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Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction ...fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO2). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO2, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA (P < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels.
•Exchange transfusions lower global CBF and OEF in SCA, suggesting transfusions reduce infarct risk by relieving cerebral metabolic stress.•In SCA, OEF is highest in the deep white matter, where infarct risk is high; transfusions reduce the volume of tissue with elevated OEF.
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Purpose
The accuracy of existing PET/MR attenuation correction (AC) has been limited by a lack of correlation between MR signal and tissue electron density. Based on our finding that longitudinal ...relaxation rate, or R1, is associated with CT Hounsfield unit in bone and soft tissues in the brain, we propose a deep learning T1‐enhanced selection of linear attenuation coefficients (DL‐TESLA) method to incorporate quantitative R1 for PET/MR AC and evaluate its accuracy and longitudinal test–retest repeatability in brain PET/MR imaging.
Methods
DL‐TESLA uses a 3D residual UNet (ResUNet) for pseudo‐CT (pCT) estimation. With a total of 174 participants, we compared PET AC accuracy of DL‐TESLA to 3 other methods adopting similar 3D ResUNet structures but using UTE R2∗, or Dixon, or T1‐MPRAGE as input. With images from 23 additional participants repeatedly scanned, the test–retest differences and within‐subject coefficient of variation of standardized uptake value ratios (SUVR) were compared between PET images reconstructed using either DL‐TESLA or CT for AC.
Results
DL‐TESLA had (1) significantly lower mean absolute error in pCT, (2) the highest Dice coefficients in both bone and air, (3) significantly lower PET relative absolute error in whole brain and various brain regions, (4) the highest percentage of voxels with a PET relative error within both ±3% and ±5%, (5) similar to CT test–retest differences in SUVRs from the cerebrum and mean cortical (MC) region, and (6) similar to CT within‐subject coefficient of variation in cerebrum and MC.
Conclusion
DL‐TESLA demonstrates excellent PET/MR AC accuracy and test–retest repeatability.
We evaluated the impact of PET respiratory motion correction (MoCo) in a phantom and patients. Moreover, we proposed and examined a PET MoCo approach using motion vector fields (MVFs) from a ...deep-learning reconstructed short MRI scan.
The evaluation of PET MoCo was performed in a respiratory motion phantom study with varying lesion sizes and tumor to background ratios (TBRs) using a static scan as the ground truth. MRI-based MVFs were derived from either 2000 spokes (MoCo
, 5-6 min acquisition time) using a Fourier transform reconstruction or 200 spokes (MoCo
, 30-40 s acquisition time) using a deep-learning Phase2Phase (P2P) reconstruction and then incorporated into PET MoCo reconstruction. For six patients with hepatic lesions, the performance of PET MoCo was evaluated using quantitative metrics (SUV
, SUV
, SUV
, lesion volume) and a blinded radiological review on lesion conspicuity.
MRI-assisted PET MoCo methods provided similar results to static scans across most lesions with varying TBRs in the phantom. Both MoCo
and MoCo
PET images had significantly higher SUV
, SUV
, SUV
and significantly lower lesion volume than non-motion-corrected (non-MoCo) PET images. There was no statistical difference between MoCo
and MoCo
PET images for SUV
, SUV
, SUV
or lesion volume. Both radiological reviewers found that MoCo
and MoCo
PET significantly improved lesion conspicuity.
An MRI-assisted PET MoCo method was evaluated using the ground truth in a phantom study. In patients with hepatic lesions, PET MoCo images improved quantitative and qualitative metrics based on only 30-40 s of MRI motion modeling data.
Purpose
Sickle cell anemia is a blood disorder that alters the morphology and the oxygen affinity of the red blood cells. Cerebral oxygen extraction fraction measurements using quantitative BOLD ...contrast have been used for assessing inadequate oxygen delivery and the subsequent risk of ischemic stroke in sickle cell anemia. The BOLD signal in MRI studies relies on Δχdo, the bulk volume susceptibility difference between fully oxygenated and fully deoxygenated blood. Several studies have measured Δχdo for normal hemoglobin A (HbA). However, it is not known whether the value is different for sickle hemoglobin. In this study, Δχdo was measured for both HbA and sickle hemoglobin.
Methods
Six sickle cell anemia patients and 6 controls were recruited. Various blood oxygenation levels were achieved through in vivo manipulations to keep the blood close to its natural state. To account for the differences in oxygen affinity, Hill’s equations were used to translate partial pressure of oxygen to oxygen saturation for HbA, sickle hemoglobin, and fetal hemoglobin (HbF) separately. The pH and PCO2 corrections were performed. Temperature and magnetic field drift were controlled for. A multivariate generalized linear mixed model with random participant effect was used.
Results
Assuming that Δχdo is similar for HbA and HbF and that ΔχmetHb is 5/4 of Δχdo for HbA, it was found that the Δχdo values for HbA and sickle hemoglobin were not statistically significantly different from each other.
Conclusion
The same Δχdo value can be used for both types of hemoglobin in quantitative BOLD analysis.
Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes ...cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (-19.4 mL/100 g/min) and OEF (-8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, -0.9 mL/100 g/min; P = .024; OEF, -3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.
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