To evaluate the contribution of germline genetics to regulating the briskness and diversity of T cell responses in CRC, we conducted a genome-wide association study to examine the associations ...between germline genetic variation and quantitative measures of T cell landscapes in 2,876 colorectal tumors from participants in the Molecular Epidemiology of Colorectal Cancer Study (MECC).
Germline DNA samples were genotyped and imputed using genome-wide arrays. Tumor DNA samples were extracted from paraffin blocks, and T cell receptor clonality and abundance were quantified by immunoSEQ (Adaptive Biotechnologies, Seattle, WA). Tumor infiltrating lymphocytes per high powered field (TILs/hpf) were scored by a gastrointestinal pathologist. Regression models were used to evaluate the associations between each variant and the three T-cell features, adjusting for sex, age, genotyping platform, and global ancestry. Three independent datasets were used for replication.
We identified a SNP (rs4918567) near RBM20 associated with clonality at a genome-wide significant threshold of 5 × 10
, with a consistent direction of association in both discovery and replication datasets. Expression quantitative trait (eQTL) analyses and in silico functional annotation for these loci provided insights into potential functional roles, including a statistically significant eQTL between the T allele at rs4918567 and higher expression of ADRA2A (P = 0.012) in healthy colon mucosa.
Our study suggests that germline genetic variation is associated with the quantity and diversity of adaptive immune responses in CRC. Further studies are warranted to replicate these findings in additional samples and to investigate functional genomic mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Physical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the ...association of cerebral white matter structure with current and future frailty.
Atherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline.
In the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk.
The current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.
Abnormal orthostatic blood pressure (BP) regulation may result in cerebral hypoperfusion and brain ischemia and contribute to dementia. It may also manifest as early symptoms of the neurodegenerative ...process associated with dementia. The relationship between the magnitude and timing of orthostatic BP responses and dementia risk is not fully understood.
We conducted a prospective cohort analysis of the associations of orthostatic BP changes and self-reported orthostatic dizziness with the risk of dementia in the Atherosclerosis Risk in Communities study (ARIC). We calculated changes in BP from the supine to the standing position at 5 measurements taken within 2 minutes after standing during the baseline visit (1987-1989). The primary outcome was adjudicated dementia ascertained through 2019.
Among 11 644 participants (mean SD age, 54.5 5.7 years; 54.1% women; 25.9% Black), 2303 dementia cases were identified during a median follow-up of 25.9 years. Large decreases in systolic BP from the supine to standing position measured at the first 2 measurements ≈30 and 50 seconds after standing, but not afterward, were associated with orthostatic dizziness and a higher risk of dementia. Comparing a decrease in systolic BP of ≤-20 or >-20 to -10 mm Hg to stable systolic BP (>-10 to 10 mm Hg) at the first measurement, the adjusted hazard ratios were 1.22 (95% CI, 1.01-1.47) and 1.10 (95% CI, 0.97-1.25), respectively.
Abnormal orthostatic BP regulation, especially abrupt drops in BP within the first minute, might be early risk markers for the development of dementia. Transient early orthostatic hypotension warrants more attention in clinical settings.
Acute exacerbation of idiopathic pulmonary fibrosis has become an important outcome measure in clinical trials. This study aimed to explore the concept of suspected acute exacerbation as an outcome ...measure.
Three investigators retrospectively reviewed subjects enrolled in the Sildenafil Trial of Exercise Performance in IPF who experienced a respiratory serious adverse event during the course of the study. Events were classified as definite acute exacerbation, suspected acute exacerbation, or other, according to established criteria.
Thirty-five events were identified. Four were classified as definite acute exacerbation, fourteen as suspected acute exacerbation, and seventeen as other. Definite and suspected acute exacerbations were clinically indistinguishable. Both were most common in the winter and spring months and were associated with a high risk of disease progression and short-term mortality.
In this study one half of respiratory serious adverse events were attributed to definite or suspected acute exacerbations. Suspected acute exacerbations are clinically indistinguishable from definite acute exacerbations and represent clinically meaningful events. Clinical trialists should consider capturing both definite and suspected acute exacerbations as outcome measures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although several monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been approved for coronavirus disease 2019 (COVID-19) therapy, development ...was generally inefficient, with lead generation often requiring the production and testing of numerous antibody candidates. Here, we report that the integration of target-ligand blocking with a previously described B cell receptor-sequencing approach (linking B cell receptor to antigen specificity through sequencing (LIBRA-seq)) enables the rapid and efficient identification of multiple neutralizing mAbs that prevent the binding of SARS-CoV-2 spike (S) protein to angiotensin-converting enzyme 2 (ACE2). The combination of target-ligand blocking and high-throughput antibody sequencing promises to increase the throughput of programs aimed at discovering new neutralizing antibodies.
We examined the relationship between baseline olfactory performance and incident significant depressive symptoms and longitudinal depression trajectories in well-functioning older adults. ...Inflammation and cognitive status were examined as potential mediators.
Older adults (n = 2 125, 71-82 years, 51% female, 37% Black) completed an odor identification task at Year 3 (our study baseline) of the Health, Aging, and Body Composition study. Cognitive assessments, depressive symptoms, and inflammatory markers were ascertained across multiple visits over 8 years. Discrete-time complementary log-log models, group-based trajectory models, and multivariable-adjusted multinomial logistic regression were employed to assess the relationship between baseline olfaction and incident depression and longitudinal depression trajectories. Mediation analysis assessed the influence of cognitive status on these relationships.
Individuals with lower olfaction had an increased risk of developing significant depressive symptoms at follow-up (hazard ratio = 1.04, 95% confidence interval CI: 1.00, 1.08). Of the 3 patterns of longitudinal depression scores identified (stable low, stable moderate, and stable high), poorer olfaction was associated with a 6% higher risk of membership in the stable moderate (relative risk ratio RRR = 1.06, 95% CI: 1.02, 1.10)/stable high (RRR = 1.06, 95% CI: 1.00, 1.12) groups, compared to the stable low group. Poor cognitive status, but not inflammation, partially mediated the relationship between olfactory performance and incident depression symptom severity.
Suboptimal olfaction could serve as a prognostic indicator of vulnerability for the development of late-life depression. These findings underscore the need for a greater understanding of olfaction in late-life depression and the demographic, cognitive, and biological factors that influence these relationships over time.
To evaluate the association between midlife plasma amyloid-β (Aβ
, Aβ
, Aβ
:Aβ
) and risk of mild cognitive impairment (MCI) and dementia.
Plasma Aβ
and Aβ
were retrospectively measured with a ...fluorometric bead-based immunoassay in a subsample of the Atherosclerosis Risk in Communities cohort study. We investigated the relationship of plasma Aβ
, Aβ
, and Aβ
:Aβ
ratio measured in midlife and late life and the change from midlife to late life to risk of MCI, dementia, and combined MCI/dementia outcomes in late life (from 2011-2019). We used multinomial logistic regressions estimating relative risk ratios (RRRs) of these cognitive outcomes vs cognitively normal adjusted for age, sex, education, site-race,
, hypertension, diabetes, and body mass index.
A total of 2,284 participants were included (midlife mean age 59.2 ± 5.2, 57% female, 22% Black). Each doubling of midlife Aβ
:Aβ
was associated with 37% lower risk of MCI/dementia (RRR 0.63, 95% confidence interval CI 0.46-0.87), but only up to approximately the median (spline model threshold 0.20). Every 1-SD increase in plasma Aβ
(10 pg/mL) was associated with 13% lower risk of MCI/dementia (RRR 0.87, 95% CI 0.77-0.98), whereas every 1-SD increase in plasma Aβ
(67 pg/mL) was associated with 15% higher risk of MCI/dementia (RRR 1.15, 95% CI 1.01-1.29). Associations were comparable but slightly weaker statistically when models were repeated using late-life plasma Aβ predictors. Aβ
and Aβ
increased from midlife to late life, but changes were not associated with cognitive outcomes.
Midlife measurement of plasma Aβ may have utility as a blood-based biomarker indicative of risk for future cognitive impairment.
1. There are few studies of the performance of species in restored vegetation communities. Here we report the results of a meta-analysis of 25 experiments concerned with species-rich grassland ...restoration on ex-arable land and agriculturally improved grasslands situated at a wide range of locations throughout lowland Britain. Differences in species' performance were related to 38 physiological and morphological traits. 2. An experiment-adjusted performance index was calculated for each of the 58 species (13 grasses and 45 forbs). The performance index was calculated for the first 4 years after establishment together with a temporal trend. 3. Individual species showed large differences in performance indices. However, grasses consistently out-performed forbs. 4. We examined the linkage between species' performance and traits according to four non-exclusive hypotheses. The ability to establish and persist in restored vegetation communities requires: (H1) good gap colonization ability; (H2) strong competitive capability; and (H3) ability to undergo vegetative regeneration. (H4) Successful species are generalists associated with fertile habitats. 5. Trait analyses supported all four hypotheses. Within the forbs, good establishment in the first year was linked to traits determining colonization ability: ruderality, percentage germination of seeds and autumn germination. However, traits linked to competitive ability, vegetative growth and seed bank persistence became increasingly important determinants of success with time. Species with generalist habitat requirements, and especially those associated with fertile soils, performed increasingly well with time. This reflects the development of a closed vegetation in which the ability to grow vigorously and out-compete other established plants is important. 6. Stress-tolerators, habitat specialists and species of infertile habitats performed badly. This may reflect high residual fertility in restored grasslands and particular niche requirements of these species. This may be a problem as grassland restoration often targets communities characterized by species with these traits and many are food plants of invertebrates of conservation value. 7. There were few significant correlations between the performance of the grasses and traits reflecting their overall good performance in comparison with the forbs. 8. This study has important implications for practical restoration programmes and policies. Efficiency might be increased by introducing only species with good performance, but this would lead to uniformity among restored grasslands and would diminish the benefits of habitat restoration for national and regional biodiversity. 9. Synthesis and applications. Future work should focus on practical methods to increase the successful establishment of the poor performing but desirable species, by (i) targeting restoration to low fertility soils, (ii) changing the abiotic environment or (iii) the 'phased introduction' of species several years after restoration, when both the plant community is more stable and the environmental conditions are more favourable for establishment.
Soil seed banks on ex‐arable land are dominated by undesirable ruderal species that compete with “desirable” target species during grassland restoration. At the same time, for continued regeneration, ...the latter often functionally depend on gap colonization from the seed bank, which serves as a buffer against local extinction. Nonetheless, few studies have so far investigated the effects of restoration practices on seed bank dynamics. Using a multisite experiment investigating techniques for restoring lowland mesotrophic grassland, we studied the effects of seedbed preparation (shallow cultivation using harrows or discs vs. deep cultivation using a plow) and of seed mixtures (species‐rich grass–forb mixes vs. species‐poor grass‐only mixes vs. unseeded natural regeneration) on 7 years of post‐restoration seed bank dynamics. We assessed how these practices affected density and diversity of sown and unsown species in the seed bank. Seed bank dynamics were much more strongly affected by seed sowing than by cultivation. Grass sowing resulted in stronger seed bank decline of unsown grasses, and additional forb sowing in stronger decline of unsown forbs. Higher seed densities and species richness of sown forbs colonizing from neighboring plots sown with the grass–forb mix were observed under natural regeneration than in the grass‐only sown treatment, reflecting grass priority effects on sown forb colonization in the latter. Sowing of diverse target species mixtures was associated with the greatest shift in seed bank composition away from extant ruderal species towards sown target species. Our results illustrate the usefulness of seed bank monitoring for assessing restoration progress.
Obesity is associated with chronic inflammation and is a risk factor for insufficient milk production. Inflammation-mediated suppression of LPL could inhibit mammary uptake of long-chain fatty acids ...(LCFAs; >16 carbons).
In an ancillary case–control analysis, we investigated whether women with low milk production despite regular breast emptying have elevated inflammation and disrupted transfer of LCFAs from plasma into milk.
Data and specimens from a low milk supply study and an exclusively breastfeeding control group were analyzed, with milk production measured by 24-h test-weighing at 2–10 wk postpartum. Low milk supply groups were defined as very low (VL; <300 mL/d; n = 23) or moderate (MOD; ≥300 mL/d; n = 20) milk production, and compared with controls (≥699 mL/d; n = 18). Serum and milk fatty acids (weight% of total) were measured by GC, serum and milk TNF-α by ELISA, and serum high-sensitivity C-reactive protein (hsCRP) by clinical analyzer. Group differences were assessed by linear regression models, chi-square exact tests, and Kruskal–Wallis nonparametric tests.
VL cases, as compared with MOD cases and controls, had higher prevalence of elevated serum hsCRP (>5 mg/L; 57%, 15%, and 22%, respectively; P = 0.004), detectable milk TNF-α (67%, 32%, and 33%, respectively; P = 0.04), and obesity (78%, 40%, and 22%, respectively; P = 0.003). VL cases had lower mean ± SD LCFAs in milk (60% ± 3%) than MOD cases (65% ± 4%) and controls (66% ± 5%) (P < 0.001). Milk and serum LCFAs were strongly correlated in controls (r = 0.82, P < 0.001), but not in the MOD (r = 0.25, P = 0.30) or VL (r = 0.20, P = 0.41) groups (Pint < 0.001).
Mothers with very low milk production have significantly higher obesity and inflammatory biomarkers, lower LCFAs in milk, and disrupted association between plasma and milk LCFAs. These data support the hypothesis that inflammation disrupts normal mammary gland fatty acid uptake. Further research should address impacts of inflammation and obesity on mammary fatty acid uptake for milk production.
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