Cell-free DNA (cfDNA) in human plasma is a class of biomarkers with many current and potential future diagnostic applications. Recent studies have shown that cfDNA molecules are not randomly ...fragmented and possess information related to their tissues of origin. Pathologies causing death of cells from particular tissues result in perturbations in the relative distribution of DNA from the affected tissues. Such tissue-of-origin analysis is particularly useful in the development of liquid biopsies for cancer. It is therefore of value to accurately determine the relative contributions of the tissues to the plasma DNA pool in a simultaneous manner. In this work, we report that in open chromatin regions, cfDNA molecules show characteristic fragmentation patterns reflected by sequencing coverage imbalance and differentially phased fragment end signals. The latter refers to differences in the read densities of sequences corresponding to the orientation of the upstream and downstream ends of cfDNA molecules in relation to the reference genome. Such cfDNA fragmentation patterns preferentially occur in tissue-specific open chromatin regions where the corresponding tissues contributed DNA into the plasma. Quantitative analyses of such signals allow measurement of the relative contributions of various tissues toward the plasma DNA pool. These findings were validated by plasma DNA sequencing data obtained from pregnant women, organ transplantation recipients, and cancer patients. Orientation-aware plasma DNA fragmentation analysis therefore has potential diagnostic applications in noninvasive prenatal testing, organ transplantation monitoring, and cancer liquid biopsy.
Cell-free DNA in human plasma is nonrandomly fragmented and reflects genomewide nucleosomal organization. Previous studies had demonstrated tissue-specific preferred end sites in plasma DNA of ...pregnant women. In this study, we performed integrative analysis of preferred end sites with the size characteristics of plasma DNA fragments. We mined the preferred end sites in short and long plasma DNA molecules separately and found that these “size-tagged” ends showed improved accuracy in fetal DNA fraction estimation and enhanced noninvasive fetal trisomy 21 testing. Further analysis revealed that the fetal and maternal preferred ends were generated from different locations within the nucleosomal structure. Hence, fetal DNA was frequently cut within the nucleosome core while maternal DNA was mostly cut within the linker region. We further demonstrated that the nucleosome accessibility in placental cells was higher than that for white blood cells, which might explain the difference in the cutting positions and the shortness of fetal DNA in maternal plasma. Interestingly, short and long size-tagged ends were also observable in the plasma of nonpregnant healthy subjects and demonstrated size differences similar to those in the pregnant samples. Because the nonpregnant samples did not contain fetal DNA, the data suggested that the interrelationship of preferred DNA ends, chromatin accessibility, and plasma DNA size profile is likely a general one, extending beyond the context of pregnancy. Plasma DNA fragment end patterns have thus shed light on production mechanisms and show utility in future developments in plasma DNA-based noninvasive molecular diagnostics.
A novel coronavirus of zoonotic origin (2019-nCoV) has recently been identified in patients with acute respiratory disease. This virus is genetically similar to SARS coronavirus and bat SARS-like ...coronaviruses. The outbreak was initially detected in Wuhan, a major city of China, but has subsequently been detected in other provinces of China. Travel-associated cases have also been reported in a few other countries. Outbreaks in health care workers indicate human-to-human transmission. Molecular tests for rapid detection of this virus are urgently needed for early identification of infected patients.
We developed two 1-step quantitative real-time reverse-transcription PCR assays to detect two different regions (ORF1b and N) of the viral genome. The primer and probe sets were designed to react with this novel coronavirus and its closely related viruses, such as SARS coronavirus. These assays were evaluated using a panel of positive and negative controls. In addition, respiratory specimens from two 2019-nCoV-infected patients were tested.
Using RNA extracted from cells infected by SARS coronavirus as a positive control, these assays were shown to have a dynamic range of at least seven orders of magnitude (2x10-4-2000 TCID50/reaction). Using DNA plasmids as positive standards, the detection limits of these assays were found to be below 10 copies per reaction. All negative control samples were negative in the assays. Samples from two 2019-nCoV-infected patients were positive in the tests.
The established assays can achieve a rapid detection of 2019n-CoV in human samples, thereby allowing early identification of patients.
Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms ...involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal-epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol-∣miRNA-520h-∣PP2A/C-∣Akt → NF-κB → FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.
A measurement of electron antineutrino oscillation by the Daya Bay Reactor Neutrino Experiment is described in detail. Six 2.9-GWth nuclear power reactors of the Daya Bay and Ling Ao nuclear power ...facilities served as intense sources of ν¯e’s. Comparison of the ν¯e rate and energy spectrum measured by antineutrino detectors far from the nuclear reactors (∼1500–1950 m) relative to detectors near the reactors (∼350–600 m) allowed a precise measurement of ν¯e disappearance. More than 2.5 million ν¯e inverse beta-decay interactions were observed, based on the combination of 217 days of operation of six antineutrino detectors (December, 2011–July, 2012) with a subsequent 1013 days using the complete configuration of eight detectors (October, 2012–July, 2015). The ν¯e rate observed at the far detectors relative to the near detectors showed a significant deficit, R=0.949±0.002(stat)±0.002(syst). The energy dependence of ν¯e disappearance showed the distinct variation predicted by neutrino oscillation. Analysis using an approximation for the three-flavor oscillation probability yielded the flavor-mixing angle sin22θ13=0.0841±0.0027(stat)±0.0019(syst) and the effective neutrino mass-squared difference of |Δmee2|=(2.50±0.06(stat)±0.06(syst))×10−3 eV2. Analysis using the exact three-flavor probability found Δm322=(2.45±0.06(stat)±0.06(syst))×10−3 eV2 assuming the normal neutrino mass hierarchy and Δm322=(−2.56±0.06(stat)±0.06(syst))×10−3 eV2 for the inverted hierarchy.
We report detection of severe acute respiratory syndrome coronavirus 2 Omicron variant (B.1.1.529) in an asymptomatic, fully vaccinated traveler in a quarantine hotel in Hong Kong, China. The Omicron ...variant was also detected in a fully vaccinated traveler staying in a room across the corridor from the index patient, suggesting transmission despite strict quarantine precautions.
Habitat loss for food production is a key threat to global biodiversity. Despite the importance of dietary choices on our capacity to mitigate the on-going biodiversity crisis, unlike with specific ...ingredients or products, consumers have limited information on the biodiversity implications of choosing to eat a certain popular dish. Here we estimated the biodiversity footprints of 151 popular local dishes from around the world when globally and locally produced and after calorical content standardization. We find that specific ingredients (beef, legumes, rice) encroaching on biodiversity hotspots with already very high agricultural pressure (e.g. India) lead to high biodiversity footprint in the dishes. Examples of high-biodiversity-footprint popular dishes were beef dishes such as fraldinha (beef cut dish) originating from Brazil and legume dishes such as chana masala (chickpea curry) from India. Regardless of assuming locally or globally produced, feedlot or pasture livestock production, vegan and vegetarian dishes presented lower biodiversity footprints than dishes containing meat. Our results demonstrate the feasibility of analysing biodiversity footprint at the dish level across multiple countries, making sustainable eating decisions more accessible to consumers.
This Letter reports an improved search for light sterile neutrino mixing in the electron antineutrino disappearance channel with the full configuration of the Daya Bay Reactor Neutrino Experiment. ...With an additional 404 days of data collected in eight antineutrino detectors, this search benefits from 3.6 times the statistics available to the previous publication, as well as from improvements in energy calibration and background reduction. A relative comparison of the rate and energy spectrum of reactor antineutrinos in the three experimental halls yields no evidence of sterile neutrino mixing in the 2×10^{-4}≲|Δm_{41}^{2}|≲0.3 eV^{2} mass range. The resulting limits on sin^{2}2θ_{14} are improved by approx imately a factor of 2 over previous results and constitute the most stringent constraints to date in the |Δm_{41}^{2}|≲0.2 eV^{2} region.
We report a new measurement of electron antineutrino disappearance using the fully constructed Daya Bay Reactor Neutrino Experiment. The final two of eight antineutrino detectors were installed in ...the summer of 2012. Including the 404 days of data collected from October 2012 to November 2013 resulted in a total exposure of 6.9×10^{5} GW_{th} ton days, a 3.6 times increase over our previous results. Improvements in energy calibration limited variations between detectors to 0.2%. Removal of six ^{241}Am-^{13}C radioactive calibration sources reduced the background by a factor of 2 for the detectors in the experimental hall furthest from the reactors. Direct prediction of the antineutrino signal in the far detectors based on the measurements in the near detectors explicitly minimized the dependence of the measurement on models of reactor antineutrino emission. The uncertainties in our estimates of sin^{2}2θ_{13} and |Δm_{ee}^{2}| were halved as a result of these improvements. An analysis of the relative antineutrino rates and energy spectra between detectors gave sin^{2}2θ_{13}=0.084±0.005 and |Δm_{ee}^{2}|=(2.42±0.11)×10^{-3} eV^{2} in the three-neutrino framework.
Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined.
We completed a comprehensive literature ...search of all published rituximab-associated HBV-R cases and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) MedWatch database. Literature and FDA cases were compared for completeness, and a meta-analysis was completed.
One hundred and eighty-three unique cases of rituximab-associated HBV-R were identified from the literature (n = 27 case reports, n = 156 case series). The time from last rituximab to reactivation was 3 months (range 0–12), although 29% occurred >6 months after last rituximab. Within FDA data (n = 118 cases), there was a strong signal for rituximab-associated HBV-R proportional reporting ratio = 28.5, 95% confidence interval (CI) 23.9–34.1; Empiric Bayes Geometric Mean = 26.4, 95% CI 21.4–31.1. However, the completeness of data in FDA reports was significantly inferior compared with literature cases (P < 0.0001). Among HBV core antibody (HBcAb(+)) series, the pooled effect of rituximab-based therapy showed a significantly increased risk of HBV-R compared with nonrituximab-treated patients (odds ratio 5.73, 95% CI 2.01–16.33; Z = 3.33, P = 0.0009) without heterogeneity (χ2 = 2.12, P = 0.5473).
The FDA AERS provided strong HBV-R safety signals; however, literature-based cases provided a significantly more complete description. Furthermore, meta-analysis of HBcAb(+) series identified a more than fivefold increased rate of rituximab-associated HBV-R.
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