Neuroinflammation in Alzheimer’s Disease Onyango, Isaac G.; Jauregui, Gretsen V.; Čarná, Mária ...
Biomedicines,
05/2021, Letnik:
9, Številka:
5
Journal Article
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Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There ...are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.
We compare the planet-to-star mass-ratio distribution measured by gravitational microlensing to core accretion theory predictions from population synthesis models. The core accretion theory's runaway ...gas accretion process predicts a dearth of intermediate-mass giant planets that is not seen in the microlensing results. In particular, the models predict ∼10 × fewer planets at mass ratios of than inferred from microlensing observations. This tension implies that gas giant formation may involve processes that have hitherto been overlooked by existing core accretion models or that the planet-forming environment varies considerably as a function of host-star mass. Variation from the usual assumptions for the protoplanetary disk viscosity and thickness could reduce this discrepancy, but such changes might conflict with microlensing results at larger or smaller mass ratios, or with other observations. The resolution of this discrepancy may have important implications for planetary habitability because it has been suggested that the runaway gas accretion process may have triggered the delivery of water to our inner solar system. So, an understanding of giant planet formation may help us to determine the occurrence rate of habitable planets.
Access to healthcare data such as electronic health records (EHR) is often restricted by laws established to protect patient privacy. These restrictions hinder the reproducibility of existing results ...based on private healthcare data and also limit new research. Synthetically-generated healthcare data solve this problem by preserving privacy and enabling researchers and policymakers to drive decisions and methods based on realistic data. Healthcare data can include information about multiple in- and out- patient visits of patients, making it a time-series dataset which is often influenced by protected attributes like age, gender, race etc. The COVID-19 pandemic has exacerbated health inequities, with certain subgroups experiencing poorer outcomes and less access to healthcare. To combat these inequities, synthetic data must “fairly” represent diverse minority subgroups such that the conclusions drawn on synthetic data are correct and the results can be generalized to real data. In this article, we develop two fairness metrics for synthetic data, and analyze all subgroups defined by protected attributes to analyze the bias in three published synthetic research datasets. These covariate-level disparity metrics revealed that synthetic data may not be representative at the univariate and multivariate subgroup-levels and thus, fairness should be addressed when developing data generation methods. We discuss the need for measuring fairness in synthetic healthcare data to enable the development of robust machine learning models to create more equitable synthetic healthcare datasets.
Glycosaminoglycans (GAGs) are essential polysaccharides in normal physiology and disease. However, understanding of the contribution of specific GAG structures to specific biological functions is ...limited, largely because of the great structural heterogeneity among GAGs themselves, as well as technical limitations in the structural characterization and chemical synthesis of GAGs. Here we describe a cell-based method to produce and display distinct GAGs with a broad repertoire of modifications, a library we refer to as the GAGOme. By using precise gene editing, we engineered a large panel of Chinese hamster ovary cells with knockout or knock-in of the genes encoding most of the enzymes involved in GAG biosynthesis, to generate a library of isogenic cell lines that differentially display distinct GAG features. We show that this library can be used for cell-based binding assays, recombinant expression of proteoglycans with distinct GAG structures, and production of distinct GAG chains on metabolic primers that may be used for the assembly of GAG glycan microarrays.
We present adaptive optics imaging from the NIRC2 instrument on the Keck II telescope that resolves the exoplanet host (and lens) star as it separates from the brighter source star. These ...observations yield the K-band brightness of the lens and planetary host star, as well as the lens-source relative proper motion, , in the heliocentric reference frame. The measurement allows for the determination of the microlensing parallax vector, , which had only a single component determined by the microlensing light curve. The combined measurements of and KL provide the masses of the host star, , and planet, mp = 3.27 0.32MJupiter with a projected separation of 3.4 0.5 au. This confirms the tentative conclusion of a previous paper that this super-Jupiter mass planet, OGLE-2005-BLG-071Lb, orbits an M dwarf. Such planets are predicted to be rare by the core accretion theory and have been difficult to find with other methods, but there are two such planets with firm mass measurements from microlensing, and an additional 11 planetary microlens events with host mass estimates and planet mass estimates >2 Jupiter masses that could be confirmed by high angular follow-up observations. We also point out that OGLE-2005-BLG-071L has separated far enough from its host star that it should be possible to measure the host-star metallicity with spectra from a high angular resolution telescope such as Keck, the Very Large Telescope, the Hubble Space Telescope, or the James Webb Space Telescope.
Although local treatments for cervical intraepithelial neoplasia (CIN) are highly effective, it has been reported that treated women remain at increased risk of cervical and other cancers. Our aim is ...to explore the risk of developing or dying from cervical cancer and other human papillomavirus (HPV)- and non-HPV-related malignancies after CIN treatment and infer its magnitude compared with the general population.
Design: Systematic review and meta-analysis. Eligibility criteria: Studies with registry-based follow-up reporting cancer incidence or mortality after CIN treatment. Data synthesis: Summary effects were estimated using random-effects models.
Incidence rate of cervical cancer among women treated for CIN (per 100 000 woman-years). Relative risk (RR) of cervical cancer, other HPV-related anogenital tract cancer (vagina, vulva, anus), any cancer, and mortality, for women treated for CIN versus the general population.
Twenty-seven studies were eligible. The incidence rate for cervical cancer after CIN treatment was 39 per 100 000 woman-years (95% confidence interval 22–69). The RR of cervical cancer was elevated compared with the general population (3.30, 2.57–4.24; P < 0.001). The RR was higher for women more than 50 years old and remained elevated for at least 20 years after treatment. The RR of vaginal (10.84, 5.58–21.10; P < 0.001), vulvar (3.34, 2.39–4.67; P < 0.001), and anal cancer (5.11, 2.73–9.55; P < 0.001) was also higher. Mortality from cervical/vaginal cancer was elevated, but our estimate was more uncertain (RR 5.04, 0.69–36.94; P = 0.073).
Women treated for CIN have a considerably higher risk to be later diagnosed with cervical and other HPV-related cancers compared with the general population. The higher risk of cervical cancer lasts for at least 20 years after treatment and is higher for women more than 50 years of age. Prolonged follow-up beyond the last screening round may be warranted for previously treated women.
•Women previously treated for CIN are at elevated risk of cervical and other HPV-related neoplasms.•Risk of cervical cancer remains elevated for at least 20 years after treatment.•Prolonged cervical screening beyond current last screening round at 60 or 65 should be considered.•Increased awareness for prevention or early cancer detection of other HPV-related malignancies is needed.
Abstract
The PRime-focus Infrared Microlensing Experiment (PRIME) will be the first to conduct a dedicated near-infrared microlensing survey by using a 1.8 m telescope with a wide field of view of ...1.45 deg
2
at the South African Astronomical Observatory. The major goals of the PRIME microlensing survey are to measure the microlensing event rate in the inner Galactic bulge to help design the observing strategy for the exoplanet microlensing survey by the Nancy Grace Roman Space Telescope and to make a first statistical measurement of exoplanet demographics in the central bulge fields where optical observations are very difficult owing to the high extinction in these fields. Here we conduct a simulation of the PRIME microlensing survey to estimate its planet yields and determine the optimal survey strategy, using a Galactic model optimized for the inner Galactic bulge. In order to maximize the number of planet detections and the range of planet mass, we compare the planet yields among four observation strategies. Assuming the Cassan et al. mass function as modified by Penny et al., we predict that PRIME will detect planetary signals for 42–52 planets (1–2 planets with
M
p
≤ 1
M
⊕
, 22−25 planets with mass 1
M
⊕
<
M
p
≤ 100
M
⊕
, 19–25 planets 100
M
⊕
<
M
p
≤ 10, 000
M
⊕
), per year depending on the chosen observation strategy.
Aims/hypothesis We determined the effects of 6 years of lifestyle intervention in persons with impaired glucose tolerance (IGT) on the development of retinopathy, nephropathy and neuropathy over a 20 ...year period. Methods In 1986, 577 adults with IGT from 33 clinics in Da Qing, China were randomly assigned by clinic to a control group or one of three lifestyle intervention groups (diet, exercise, and diet plus exercise). Active intervention was carried out from 1986 to 1992. In 2006 we conducted a 20 year follow-up study of the original participants to compare the incidence of microvascular complications in the combined intervention group vs the control group. Results Follow-up information was obtained on 542 (94%) of the 577 original participants. The cumulative incidence of severe retinopathy was 9.2% in the combined intervention group and 16.2% in the control group (p = 0.03, log-rank test). After adjusting for clinic and age, the incidence of severe retinopathy was 47% lower in the intervention group than the control group (hazard rate ratio 0.53, 95% CI 0.29-0.99, p = 0.048). No significant differences were found in the incidence of severe nephropathy (hazard rate ratio 1.05, 95% CI 0.16-7.05, intervention vs control, p = 0.96) or in the prevalence of neuropathy (8.6% vs 9.1%, p = 0.89) among the 20 year survivors. Conclusions/interpretation Lifestyle intervention for 6 years in IGT was associated with a 47% reduction in the incidence of severe, vision-threatening retinopathy over a 20 year interval, primarily due to the reduced incidence of diabetes in the intervention group. However, similar benefits were not seen for nephropathy or neuropathy.
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