Migration of activated regulatory T (Treg) cells to inflamed tissue is crucial for their immune-modulatory function. While metabolic reprogramming during Treg cell differentiation has been ...extensively studied, the bioenergetics of Treg cell trafficking remains undefined. We have investigated the metabolic demands of migrating Treg cells in vitro and in vivo. We show that glycolysis was instrumental for their migration and was initiated by pro-migratory stimuli via a PI3K-mTORC2-mediated pathway culminating in induction of the enzyme glucokinase (GCK). Subsequently, GCK promoted cytoskeletal rearrangements by associating with actin. Treg cells lacking this pathway were functionally suppressive but failed to migrate to skin allografts and inhibit rejection. Similarly, human carriers of a loss-of-function GCK regulatory protein gene—leading to increased GCK activity—had reduced numbers of circulating Treg cells. These cells displayed enhanced migratory activity but similar suppressive function, while conventional T cells were unaffected. Thus, GCK-dependent glycolysis regulates Treg cell migration.
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•Migration of regulatory T (Treg) cells requires glycolysis•This is mediated by the enzyme glucokinase induced by a PI3K-mTORC2 pathway•Treg cells lacking this pathway are unable to localize to inflammatory sites•A loss-of-function GCK regulator gene causes enhanced motility of human Treg cells
Regulatory T cell localization to inflammatory sites is key to their homeostatic function. Kishore and colleagues demonstrate that Treg cell migration requires the activation of glycolysis by the enzyme glucokinase induced via a Treg cell-selective PI3K-mTORC2 pathway.
In understanding the nature of contrast in the emerging field of neutral helium microscopy, it is important to identify if there is an atom-surface scattering distribution that can be expected to ...apply broadly across a range of sample surfaces. Here we present results acquired in a scanning helium microscope (SHeM) under typical operating conditions, from a range of surfaces in their native state,
i.e.
without any specialist sample preparation. We observe diffuse scattering, with an approximately cosine distribution centred about the surface normal. The 'cosine-like' distribution is markedly different from those distributions observed from the well-prepared, atomically pristine, surfaces typically studied in helium atom scattering experiments. Knowledge of the typical scattering distribution in SHeM experiments provides a starting basis for interpretation of topographic contrast in images, as well as a reference against which more exotic contrast mechanisms can be compared.
By studying well defined geometries (microspheres) in scanning helium microscopy (SHeM) the default scattering distribution for technological surfaces in SHeM is found to be diffuse and approximately cosine.
Once thawed, up to 15% of the ∼1,000 Pg of organic carbon (C) in arctic permafrost soils may be oxidized to carbon dioxide (CO2) by 2,100, amplifying climate change. However, predictions of this ...amplification strength ignore the oxidation of permafrost C to CO2 in surface waters (photomineralization). We characterized the wavelength dependence of permafrost dissolved organic carbon (DOC) photomineralization and demonstrate that iron catalyzes photomineralization of old DOC (4,000–6,300 a BP) derived from soil lignin and tannin. Rates of CO2 production from photomineralization of permafrost DOC are twofold higher than for modern DOC. Given that model predictions of future net loss of ecosystem C from thawing permafrost do not include the loss of CO2 to the atmosphere from DOC photomineralization, current predictions of an average of 208 Pg C loss by 2,299 may be too low by ~14%.
Plain Language Summary
The thawing of organic carbon stored in arctic permafrost soils, and its oxidation to carbon dioxide (a greenhouse gas), is predicted to be a major, positive feedback on global warming. However, current estimates of the magnitude of this feedback do not include the oxidation of permafrost soil organic carbon flushed to sunlit lakes and rivers. Here we show that ancient dissolved organic carbon (>4,000 years old) draining permafrost soils is readily oxidized to carbon dioxide by sunlight. As a consequence, current estimates of additional global warming from the permafrost carbon feedback are too low.
Key Points
Wavelength dependence of permafrost dissolved organic carbon (DOC) photomineralization revealed a high lability to visible light
Iron catalyzes the photomineralization of old permafrost DOC (>4,000 a BP) derived from soil lignin and tannin to carbon dioxide (CO2)
Photomineralization rates of permafrost DOC to CO2 are double that of modern DOC, which will increase future arctic amplification
We present the achievements of the last years of the experimental and theoretical groups working on hadronic cross section measurements at the low-energy
e
+
e
−
colliders in Beijing, Frascati, ...Ithaca, Novosibirsk, Stanford and Tsukuba and on
τ
decays. We sketch the prospects in these fields for the years to come. We emphasise the status and the precision of the Monte Carlo generators used to analyse the hadronic cross section measurements obtained as well with energy scans as with radiative return, to determine luminosities and
τ
decays. The radiative corrections fully or approximately implemented in the various codes and the contribution of the vacuum polarisation are discussed.
Stereotactic ablative radiation therapy (SABR) is a guideline-specified treatment option for early-stage lung cancer. However, significant posttreatment fibrosis can occur and obfuscate the detection ...of local recurrence. The goal of this study was to assess physician ability to detect timely local recurrence and to compare physician performance with a radiomics tool.
Posttreatment computed tomography (CT) scans (n=182) from 45 patients treated with SABR (15 with local recurrence matched to 30 with no local recurrence) were used to measure physician and radiomic performance in assessing response. Scans were individually scored by 3 thoracic radiation oncologists and 3 thoracic radiologists, all of whom were blinded to clinical outcomes. Radiomic features were extracted from the same images. Performances of the physician assessors and the radiomics signature were compared.
When taking into account all CT scans during the whole follow-up period, median sensitivity for physician assessment of local recurrence was 83% (range, 67%-100%), and specificity was 75% (range, 67%-87%), with only moderate interobserver agreement (κ = 0.54) and a median time to detection of recurrence of 15.5 months. When determining the early prediction of recurrence within <6 months after SABR, physicians assessed the majority of images as benign injury/no recurrence, with a mean error of 35%, false positive rate (FPR) of 1%, and false negative rate (FNR) of 99%. At the same time point, a radiomic signature consisting of 5 image-appearance features demonstrated excellent discrimination, with an area under the receiver operating characteristic curve of 0.85, classification error of 24%, FPR of 24%, and FNR of 23%.
These results suggest that radiomics can detect early changes associated with local recurrence that are not typically considered by physicians. This decision support system could potentially allow for early salvage therapy of patients with local recurrence after SABR.
To compare volumetric MRI of whole brain and medial temporal lobe structures to clinical measures for predicting progression from amnestic mild cognitive impairment (MCI) to Alzheimer disease (AD).
...Baseline MRI scans from 129 subjects with amnestic MCI were obtained from participants in the Alzheimer's Disease Cooperative Study group's randomized, placebo-controlled clinical drug trial of donepezil, vitamin E, or placebo. Measures of whole brain, ventricular, hippocampal, and entorhinal cortex volumes were acquired. Participants were followed with clinical and cognitive evaluations until formal criteria for AD were met, or completion of 36 months of follow-up. Logistic regression modeling was done to assess the predictive value of all MRI measures, risk factors such as APOE genotype, age, family history of AD, education, sex, and cognitive test scores for progression to AD. Least angle regression modeling was used to determine which variables would produce an optimal predictive model, and whether adding MRI measures to a model with only clinical measures would improve predictive accuracy.
Of the four MRI measures evaluated, only ventricular volumes and hippocampal volumes were predictive of progression to AD. Maximal predictive accuracy using only MRI measures was obtained by hippocampal volumes by themselves (60.4%). When clinical variables were added to the model, the predictive accuracy increased to 78.8%. Use of MRI measures did not improve predictive accuracy beyond that obtained by cognitive measures alone. APOE status, MRI, or demographic variables were not necessary for the optimal predictive model. This optimal model included the Delayed 10-word list recall, New York University Delayed Paragraph Recall, and the Alzheimer's Disease Assessment Scale-Cognitive Subscale total score.
In moderate stages of amnestic mild cognitive impairment, common cognitive tests provide better predictive accuracy than measures of whole brain, ventricular, entorhinal cortex, or hippocampal volumes for assessing progression to Alzheimer disease.
To determine whether an fMRI memory encoding task distinguishes among cognitively normal elderly individuals, patients with mild cognitive impairment (MCI), and patients with early Alzheimer's ...disease (AD).
Twenty-nine subjects (11 normal, 9 MCI, 9 AD) were studied with an fMRI memory encoding task. A passive sensory task was also performed to assess potential intergroup differences in fMRI responsiveness. Activation in the medial temporal lobe for the memory task and in the anatomic rolandic area for the sensory task was studied. Intergroup comparisons were performed using receiver operating characteristic (ROC) analyses. The ROC method provides rigorous control of artifactual false-positive "activation." Subjects were tested for recall and recognition of the encoding task stimuli following the fMRI study.
Medial temporal lobe activation was greater in normal subjects than MCI and AD patients (p = 0.03 and p = 0.04). There was no difference between AD and MCI patients in fMRI memory performance corrected. There was an association between fMRI memory activation (area under the ROC curve) and post-fMRI performance on recognition and free recall. There was no difference among the three groups on the sensory task.
MCI and AD patients had less medial temporal lobe activation on the memory task than the normal subjects but similar activation as normal subjects on the sensory task. These findings suggest decreased medial temporal activation may be a specific marker of limbic dysfunction due to the neurodegenerative changes of AD. In addition, fMRI is sufficiently sensitive to detect changes in the prodromal, MCI, phase of the disease.
International evidence suggests that green space has beneficial effects on general and mental health but little is known about how lifetime exposure to green space influences cognitive ageing. ...Employing a novel longitudinal life course approach, we examined the association between lifetime availability of public parks and cognitive ageing. Lifetime residential information was gathered from the participants of the Lothian Birth Cohort 1936 using a “life-grid” questionnaire at age 78 years. Parks information from 1949, 1969 and 2009 was used to determine a percentage of parks within a 1500 m buffer zone surrounding residence for childhood, adulthood, and later adulthood periods. Linear regressions were undertaken to test for association with age-standardised, residualised change in cognitive function (Moray House Test score) from age 11 to 70 years, and from age 70 to 76 (n = 281). The most appropriate model was selected using the results of a partial F-test, and then stratified by demographic, genetic and socioeconomic factors. The local provision of park space in childhood and adulthood were both important in explaining the change in cognitive function in later life. The association between childhood and adulthood park availability and change in the Moray House Test Score from age 70 to 76 was strongest for women, those without an APOE e4 allele (a genetic risk factor), and those in the lowest socioeconomic groups.
Greater neighbourhood provision of public parks from childhood through to adulthood may help to slow down the rate of cognitive decline in later life, recognising that such environmental associations are always sensitive to individual characteristics.
•Lifecourse approaches are necessary to investigate green space and cognitive ageing.•Better cognitive ageing depended on more park provision in childhood and adulthood.•Childhood park provision was modified by adulthood park provision.•Association was strongest in females, without an APOE e4 alelle and in a lower SES.
The polycomb repressive complex 2 (PRC2) is a highly conserved histone H3 lysine 27 methyltransferase that regulates the expression of developmental genes. Inactivating mutations of the catalytic ...component of PRC2, EZH2, are seen in myeloid disorders. We reasoned that the other 2 core PRC2 components, SUZ12 and EED, may also be mutational targets in these diseases, as well as associated factors such as JARID2. SUZ12 mutations were identified in 1 of 2 patients with myelodysplastic syndrome/myeloproliferative neoplasms with 17q acquired uniparental disomy and in 2 of 2 myelofibrosis cases with focal 17q11 deletions. All 3 were missense mutations affecting the highly conserved VEFS domain. Analysis of a further 146 myelodysplastic syndrome/myeloproliferative neoplasm patients revealed an additional VEFS domain mutant, yielding a total mutation frequency of 1.4% (2 of 148). We did not find mutations of JARID2 or EED in association with acquired uniparental disomy for chromosome 6p or 11q, respectively; however, screening unselected cases identified missense mutations in EED (1 of 148; 1%) and JARID2 (3 of 148; 2%). All 3 SUZ12 mutations tested and the EED mutation reduced PRC2 histone methyltransferase activity in vitro, demonstrating that PRC2 function may be compromised in myeloid disorders by mutation of distinct genes.
Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index ...(BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality.
We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies.
The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in 'severe' patients (pooled OR 0.33 (0.23 to 0.48), p<0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6 min walk distance (6MWD) or lung function decline.
The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.
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