Abstract Background Proteins pathogenic in Alzheimer's disease (AD) were extracted from neurally derived blood exosomes and quantified to develop biomarkers for the staging of sporadic AD. Methods ...Blood exosomes obtained at one time-point from patients with AD (n = 57) or frontotemporal dementia (FTD) (n = 16), and at two time-points from others (n = 24) when cognitively normal and 1 to 10 years later when diagnosed with AD were enriched for neural sources by immunoabsorption. AD-pathogenic exosomal proteins were extracted and quantified by enzyme-linked immunosorbent assays. Results Mean exosomal levels of total tau, P-T181-tau, P-S396-tau, and amyloid β 1–42 (Aβ1–42) for AD and levels of P-T181-tau and Aβ1–42 for FTD were significantly higher than for case-controls. Step-wise discriminant modeling incorporated P-T181-tau, P-S396-tau, and Aβ1–42 in AD, but only P-T181-tau in FTD. Classification of 96.4% of AD patients and 87.5% of FTD patients was correct. In 24 AD patients, exosomal levels of P-S396-tau, P-T181-tau, and Aβ1–42 were significantly higher than for controls both 1 to 10 years before and when diagnosed with AD. Conclusions Levels of P-S396-tau, P-T181-tau, and Aβ1–42 in extracts of neurally derived blood exosomes predict the development of AD up to 10 years before clinical onset.
MHC class II (MHCII) expression is usually restricted to APC but can be expressed by cancer cells. We examined the effect of cancer cell-specific MHCII (csMHCII) expression in lung adenocarcinoma on ...T cell recruitment to tumors and response to anti-PD-1 therapy using two orthotopic immunocompetent murine models of non-small cell lung cancer: CMT167 (CMT) and Lewis lung carcinoma (LLC). We previously showed that CMT167 tumors are eradicated by anti-PD1 therapy, whereas LLC tumors are resistant. RNA sequencing analysis of cancer cells recovered from tumors revealed that csMHCII correlated with response to anti-PD1 therapy, with immunotherapy-sensitive CMT167 cells being csMHCII positive, whereas resistant LLC cells were csMHCII negative. To test the functional effects of csMHCII, MHCII expression was altered on the cancer cells through loss- and gain-of-function of CIITA, a master regulator of the MHCII pathway. Loss of CIITA in CMT167 decreased csMHCII and converted tumors from anti-PD-1 sensitive to anti-PD-1 resistant. This was associated with lower levels of Th1 cytokines, decreased T cell infiltration, increased B cell numbers, and decreased macrophage recruitment. Conversely, overexpression of CIITA in LLC cells resulted in csMHCII in vitro and in vivo. Enforced expression of CIITA increased T cell infiltration and sensitized tumors to anti-PD-1 therapy. csMHCII expression was also examined in a subset of surgically resected human lung adenocarcinomas by multispectral imaging, which provided a survival benefit and positively correlated with T cell infiltration. These studies demonstrate a functional role for csMHCII in regulating T cell infiltration and sensitivity to anti-PD-1.
ABSTRACT
We report a study exploring how the use of deep neural networks with astronomical Big Data may help us find and uncover new insights into underlying phenomena: through our experiments ...towards unsupervised knowledge extraction from astronomical Big Data we serendipitously found that deep convolutional autoencoders tend to reject telluric lines in stellar spectra. With further experiments, we found that only when the spectra are in the barycentric frame does the network automatically identify the statistical independence between two components, stellar versus telluric, and rejects the latter. We exploit this finding and turn it into a proof-of-concept method for removal of the telluric lines from stellar spectra in a fully unsupervised fashion: we increase the interobservation entropy of telluric absorption lines by imposing a random, virtual radial velocity to the observed spectrum. This technique results in a non-standard form of ‘whitening’ in the atmospheric components of the spectrum, decorrelating them across multiple observations. We process more than 250 000 spectra from the High Accuracy Radial velocity Planetary Search and with qualitative and quantitative evaluations against a data base of known telluric lines, show that most of the telluric lines are successfully rejected. Our approach, ‘Stellar Karaoke’, has zero need for prior knowledge about parameters such as observation time, location, or the distribution of atmospheric molecules and processes each spectrum in milliseconds. We also train and test on Sloan Digital Sky Survey and see a significant performance drop due to the low resolution. We discuss directions for developing tools on top of the introduced method in the future.
Men diagnosed with nonmetastatic prostate cancer have a long life expectancy, and many die of unrelated causes. It is therefore important to know to what extent post-diagnostic diet may affect ...disease-specific and overall mortality. A total of 926 men participating in the Physicians' Health Study diagnosed with nonmetastatic prostate cancer completed diet questionnaires for a median of 5.1 years after diagnosis, and were followed thereafter to assess mortality for a median of 9.9 years since questionnaire completion. Two post-diagnostic dietary patterns were identified: a Prudent pattern, characterized by higher intake of vegetables, fruits, fish, legumes, and whole grains; and a Western pattern, characterized by higher intake of processed and red meats, high-fat dairy and refined grains. Cox regression was used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). During 8,093 person-years of follow-up, 333 men died, 56 (17%) of prostate cancer. The Western pattern was significantly related to a higher risk of prostate cancer-specific and all-cause mortality. Comparing men in the highest versus the lowest quartile of the Western pattern, the HRs were 2.53 (95% CI, 1.00-6.42; Ptrend = 0.02) for prostate cancer-specific mortality and 1.67 (95% CI, 1.16-2.42; Ptrend = 0.01) for all-cause mortality. The Prudent pattern was associated with a significantly lower all-cause mortality (HRQuartile 4 vs. Quartile 1: 0.64; 95% CI, 0.44-0.93; Ptrend = 0.02); the relationship with prostate cancer-specific mortality was inverse but not statistically significant. A post-diagnostic Western dietary pattern was associated with higher prostate cancer-specific and all-cause mortality, whereas a Prudent dietary pattern was related to lower all-cause mortality after prostate cancer diagnosis.
Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates β-catenin concentrations, resulting in increased oncogene expression. ...The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40).
Abstract
HS Hydrae is a short period eclipsing binary (
P
orb
= 1.57 day) that belongs to a rare group of systems observed to have rapidly changing inclinations. This evolution is due to a third star ...on an intermediate orbit, and results in significant differences in eclipse depths and timings year to year. Zasche & Paschke revealed that HS Hydrae’s eclipses were rapidly fading from view, predicting they would cease around 2022. Using 25 days of photometric data from Sector 009 of the Transiting Exoplanet Survey Satellite (TESS), we find that the primary eclipses for HS Hydrae were only 0.00173 ± 0.00007 mag in depth in March 2019. This data from TESS likely represents the last eclipses detected from HS Hydrae. We also searched the Digitization of the Harvard Astronomical Plate Collection archive for historic data from the system. With a total baseline of over 125 yr, this unique combination of data sets—from photographic plates to precision space-based photometry—allows us to trace the emergence and decay of eclipses from HS Hydrae, and further constrain its evolution. Recent TESS observations from Sector 035 confirm that eclipses have ceased for HS Hya, and we estimate they will begin again in 2195.
Herein, we report the catalytic allylic amination of α-methylalkenes with V2O3Dipic2(HMPA)2 and chloramine T as the quantitative source of N. The reaction works with high yields and ...stereoselectivities for α-methylalkenes. A proposed tosylnitrene-free catalytic cycle involving the formation of vanadoxaziridine complex 1 as the active catalyst and aminovanadation across the substrate as the rate-determining step has been proposed. Initial kinetic and competition experiments provide evidence for the proposed mechanism.
Introduction to Volume 16 Issue 1 Edyburn, Dave; Howard, Erin L
Assistive technology outcomes and benefits,
01/2022, Letnik:
16, Številka:
1
Journal Article
Recenzirano
The timing of this work was auspicious as many authors were able to collect data during the initial days of the pivot from classroom-based instruction to remote learning (March 2020), as well as the ...start of the new school year when the Delta variant began surging (Fall 2021) and the emergence of the Omicron variant in December 2021 (Center for Disease Control and Prevention, 2021). In the first article, Assistive Technology/Augmentative & Alternative Communication Implementation: School to Home during COVID-19, authors Corduff, Lee, Rockinson-Szapkiw and Watson report on the results of a mixed methods study involving a national survey designed to understand the processes special educators, schools, and districts used to implement assistive technology (AT) and augmentative and alternative communication (AAC) tools during the pivot from face-to-face (F2F) instruction to virtual instruction during the COVID-19 pandemic. In their article, Virtual Parent Education on Assistive Technology: Pandemic Lessons Learned, they report on the results of a virtual parent education program designed to assist in preparing parents of students with learning disabilities as their child transitioned from one school to another to address the concern that the transition would be seamless regarding the support and use of assistive technologies. The findings add to the existing literature that demonstrates parent improvement in navigating special education systems, advances in special education knowledge, and family empowerment following direct training in special education law and advocacy skills.
Several lifestyle factors have been associated with risk of lethal prostate cancer, but little is known about their combined effect. Our objective was to develop and apply a lifestyle score for ...prevention of lethal prostate cancer.
We developed a lifestyle score among 42 701 men in the Health Professionals Follow-up Study (HPFS) followed from 1986 to 2010 and applied it among 20 324 men in the Physicians' Health Study (PHS) followed from 1982 to 2010. One point was given for each of: not currently smoking or quit 10 or more years ago, body mass index under 30 kg/m(2), high vigorous physical activity, high intake of tomatoes and fatty fish, and low intake of processed meat. Diet-only scores (range = 0-3) and total scores (range = 0-6) were calculated. We used multivariable Cox proportional hazards regression to estimate the risk of lethal prostate cancer, adjusting for potential risk factors of lethal prostate cancer. All statistical tests were two-sided.
We observed 576 lethal prostate cancer events in HPFS and 337 in PHS. Men with 5-6 vs 0-1 points had a 68% decreased risk of lethal prostate cancer (hazard ratio HR = 0.32, 95% confidence interval CI = 0.19 to 0.52) in HPFS and a non-statistically significant 38% decreased risk (HR = 0.62, 95% CI = 0.30 to 1.26) in PHS. For dietary factors only, men with 3 vs 0 points had a 46% decreased risk (HR = 0.54, 95% CI = 0.30 to 0.96) in the HPFS and a non-statistically significant 30% decreased risk (HR = 0.70, 95% CI = 0.40 to 1.23) in PHS.
Adhering to a healthy lifestyle, defined by not smoking, normal body weight, high physical activity, and a healthy diet, may lower risk of lethal prostate cancer.
Herein we report the WO
Dipic(H
O) promoted oxyamination of alkenes using sulfonamides as the quantitative source of
. The reaction works for activated and unactivated alkenes in high yields, ...diastereoselectivities, and stereospecificity. A catalytic cycle involving the formation of tungstenooxaziridine complex 1 as the active catalyst and hydrolysis of tungstenooxazolidine intermediate
as the rate-determining-step has been proposed. Initial kinetic and competition experiments provide evidence for the proposed mechanism.
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