Volunteers were required to estimate 10-s intervals after 2.5 min exposures to each of six different patterns of complex magnetic fields. The approximately 10 μT fields were applied sequentially ...through eight solenoids that were arranged circumcerebrally (every 45 deg) at the level of the temporoorbital plane. There were three rates of change for the circumcerebral rotations whose durations ranged between about 200 and 2000 ms. Successive additions of 20 ms of the complex fields during the counterclockwise circumcerebral rotation at each solenoid distended subjective time most effectively. Subjective time of the group who received these counterclockwise rotations was about 3 s longer than the group who received the clockwise rotations (explaining approximately 50% of the variance). The results are consistent with the model that the temporal binding for experience, most likely a feature of the rostrocaudal waves recreated every approximately 20 ms over the cerebral cortices, can be modified by weak magnetic fields whose spatial direction and temporal complexity are designed to interact with this process.
Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the human genome. Instead, different human genomic regions vary by up to fivefold ...in the local density of cancer somatic mutations, posing a fundamental problem for statistical methods used in cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific. We investigated the distribution of mutations in multiple independent samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. The best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of matched cancer cell lines. Furthermore, we show that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, the DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.
We present the impact tests that preceded the most recent operational upgrades to the land surface model used in the National Centers for Environmental Prediction (NCEP) mesoscale Eta model, whose ...operational domain includes North America. These improvements consist of changes to the “Noah” land surface model (LSM) physics, most notable in the area of cold season processes. Results indicate improved performance in forecasting low‐level temperature and humidity, with improvements to (or without affecting) the overall performance of the Eta model quantitative precipitation scores and upper air verification statistics. Remaining issues that directly affect the Noah LSM performance in the Eta model include physical parameterizations of radiation and clouds, which affect the amount of available energy at the surface, and stable boundary layer and surface layer processes, which affect surface turbulent heat fluxes and ultimately the surface energy budget.
Lipoprotein (a) Lp(a) is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential ...mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions with and without correction for Lp(a)-cholesterol at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced.
The purpose of this study was assess the effect of evolocumab (AMG 145) on lipoprotein (Lp)(a) from a pooled analysis of 4 phase II trials.
Lp(a), a low-density lipoprotein (LDL) particle linked to ...the plasminogen-like glycoprotein apolipoprotein(a), shows a consistent and independent positive association with cardiovascular disease risk in epidemiological studies. Current therapeutic options to reduce Lp(a) are limited.
A pooled analysis of data from 1,359 patients in 4 phase II trials assessed the effects of evolocumab, a fully human monoclonal antibody to PCSK9, on Lp(a), the relationship between Lp(a) and lowering of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B, and the influence of background statin therapy. Lp(a) was measured using a standardized isoform-independent method.
Evolocumab treatment for 12 weeks resulted in significant (p < 0.001) mean (95% confidence interval) dose-related reductions in Lp(a) compared to control: 29.5% (23.3% to 35.7%) and 24.5% (20.4% to 28.7%) with 140 mg and 420 mg, dosed every 2 and 4 weeks, respectively, with no plateau of effect. Lp(a) reductions were significantly correlated with percentages of reductions in LDL-C (Spearman correlation coefficient, 0.5134; p < 0.001) and apolipoprotein B (Spearman correlation coefficient, 0.5203; p < 0. 001). Mean percentage reductions did not differ based on age or sex but the trend was greater in those patients taking statins.
Inhibition of PCSK9 with evolocumab resulted in significant dose-related reductions in Lp(a). While the mean percentage of reduction was significantly greater in those patients with baseline Lp(a) of ≤125 nmol/l, the absolute reduction was substantially larger in those with levels >125 nmol/l.
Epigenetic patterns in a complete human genome Gershman, Ariel; Sauria, Michael E G; Guitart, Xavi ...
Science (American Association for the Advancement of Science),
04/2022, Letnik:
376, Številka:
6588
Journal Article
Recenzirano
Odprti dostop
The completion of a telomere-to-telomere human reference genome, T2T-CHM13, has resolved complex regions of the genome, including repetitive and homologous regions. Here, we present a high-resolution ...epigenetic study of previously unresolved sequences, representing entire acrocentric chromosome short arms, gene family expansions, and a diverse collection of repeat classes. This resource precisely maps CpG methylation (32.28 million CpGs), DNA accessibility, and short-read datasets (166,058 previously unresolved chromatin immunoprecipitation sequencing peaks) to provide evidence of activity across previously unidentified or corrected genes and reveals clinically relevant paralog-specific regulation. Probing CpG methylation across human centromeres from six diverse individuals generated an estimate of variability in kinetochore localization. This analysis provides a framework with which to investigate the most elusive regions of the human genome, granting insights into epigenetic regulation.
The distributed model intercomparison project (DMIP) was formulated as a broad comparison of many distributed models amongst themselves and to a lumped model used for operational river forecasting in ...the US. DMIP was intended to provide guidance on research and implementation directions for the US National Weather Service as well as to address unresolved questions on the variability of rainfall and its effect on basin response. Twelve groups participated, including groups from Canada, China, Denmark, New Zealand, and the US. Numerous data sets including seven years of concurrent radar-rainfall and streamflow data were provided to participants through web access. Detailed modeling instructions specified calibration and verification periods and modeling points. Participating models were run in ‘simulation’ mode without a forecast component. DMIP proved to be a successful endeavour, providing the hydrologic research and forecasting communities with a wealth of results. This paper presents the background and motivations for DMIP and describes the major project elements.
The presence of optocouplers, tyristors, Triac switches, and light-emitting diodes within complex electronic circuits that generated magnetic fields within volumes in which living systems are exposed ...may create the conditions for non-local production of photons within those volumes. Because the power densities of biophotons that mediate inter-cell communication within organisms and potentially control cell proliferation are similar to those for cosmic rays, terrestrial sources of photons, and light emissions during human cognition, this non-locality would involve a field of subtle energies. Calculations show remarkable convergence between current densities and power values within the optocoupler components and the characteristics of photons within conditions that could promote excess correlations and non-locality including the involvement of Casimir forces. Spectral analyses of the computer-generated signals that produced the magnetic field through either the optocoupler or an alternative circuit revealed higher frequency durations in the order of 20 to 40 ms of "absent signals" that could affect the type of base nucleotide sequencing. The quantitative solutions suggest that under certain conditions the four-dimensional magnetic field within which the animal is exposed during effective treatments of anomalous cell proliferation serves as a dynamic "containment" analogous to a coherent domain where photonic patterns between the electronic equipment and living system are coupled.
The presence of optocouplers, tyristors, Triac switches, and light-emitting diodes within complex electronic circuits that generated magnetic fields within volumes in which living systems are exposed ...may create the conditions for non-local production of photons within those volumes. Because the power densities of biophotons that mediate inter-cell communication within organisms and potentially control cell proliferation are similar to those for cosmic rays, terrestrial sources of photons, and light emissions during human cognition, this non-locality would involve a field of subtle energies. Calculations show remarkable convergence between current densities and power values within the optocoupler components and the characteristics of photons within conditions that could promote excess correlations and non-locality including the involvement of Casimir forces. Spectral analyses of the computer-generated signals that produced the magnetic field through either the optocoupler or an alternative circuit revealed higher frequency durations in the order of 20 to 40 ms of “absent signals” that could affect the type of base nucleotide sequencing. The quantitative solutions suggest that under certain conditions the four-dimensional magnetic field within which the animal is exposed during effective treatments of anomalous cell proliferation serves as a dynamic “containment” analogous to a coherent domain where photonic patterns between the electronic equipment and living system are coupled.
The presence of optocouplers, tyristors, Triac switches, and light-emitting diodes within complex electronic circuits that generated magnetic fields within volumes in which living systems are exposed ...may create the conditions for non-local production of photons within those volumes. Because the power densities of biophotons that mediate inter-cell communication within organisms and potentially control cell proliferation are similar to those for cosmic rays, terrestrial sources of photons, and light emissions during human cognition, this non-locality would involve a field of subtle energies. Calculations show remarkable convergence between current densities and power values within the optocoupler components and the characteristics of photons within conditions that could promote excess correlations and non-locality including the involvement of Casimir forces. Spectral analyses of the computer-generated signals that produced the magnetic field through either the optocoupler or an alternative circuit revealed higher frequency durations in the order of 20 to 40 ms of “absent signals” that could affect the type of base nucleotide sequencing. The quantitative solutions suggest that under certain conditions the four-dimensional magnetic field within which the animal is exposed during effective treatments of anomalous cell proliferation serves as a dynamic “containment” analogous to a coherent domain where photonic patterns between the electronic equipment and living system are coupled.
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