RNA Pol II pausing facilitates phased pluripotency transitions by buffering transcription.

Promoter-proximal RNA Pol II pausing is a critical step in transcriptional control. Pol II pausing has been predominantly studied in tissue culture systems. While Pol II pausing has been shown to be required for mammalian development, the phenotypic and mechanistic details of this requirement are unknown. Here, we found that loss of Pol II pausing stalls pluripotent state transitions within the epiblast of the early mouse embryo. Using Nelfb -/- mice and a NELFB degron mouse pluripotent stem cell model, we show that embryonic stem cells (ESCs) representing the naïve state of pluripotency successfully initiate a transition program but fail to balance levels of induced and repressed genes and enhancers in the absence of NELF. We found an increase in chromatin-associated NELF during transition from the naïve to later pluripotent states. Overall, our work defines the acute and long-term molecular consequences of NELF loss and reveals a role for Pol II pausing in the pluripotency continuum as a modulator of cell state transitions.

Model-based characterization of the equilibrium dynamics of transcription initiation and promoter-proximal pausing in human cells.

In metazoans, both transcription initiation and the escape of RNA polymerase (RNAP) from promoter-proximal pausing are key rate-limiting steps in gene expression. These processes play out at physically proximal sites on the DNA template and appear to influence one another through steric interactions. Here, we examine the dynamics of these processes using a combination of statistical modeling, simulation, and analysis of real nascent RNA sequencing data. We develop a simple probabilistic model that jointly describes the kinetics of transcription initiation, pause-escape, and elongation, and the generation of nascent RNA sequencing read counts under steady-state conditions. We then extend this initial model to allow for variability across cells in promoter-proximal pause site locations and steric hindrance of transcription initiation from paused RNAPs. In an extensive series of simulations, we show that this model enables accurate estimation of initiation and pause-escape rates. Furthermore, we show by simulation and analysis of real data that pause-escape is often strongly rate-limiting and that steric hindrance can dramatically reduce initiation rates. Our modeling framework is applicable to a variety of inference problems, and our software for estimation and simulation is freely available.

Canalization of Phenotypes-When the Transcriptome is Constantly but Weakly Perturbed.

Recent studies have increasingly pointed to microRNAs (miRNAs) as the agent of gene regulatory network (GRN) stabilization as well as developmental canalization against constant but small environmental perturbations. To analyze mild perturbations, we construct a Dicer-1 knockdown line (dcr-1 KD) in Drosophila that modestly reduces all miRNAs by, on average, ∼20%. The defining characteristic of stabilizers is that, when their capacity is compromised, GRNs do not change their short-term behaviors. Indeed, even with such broad reductions across all miRNAs, the changes in the transcriptome are very modest during development in stable environment. By comparison, broad knockdowns of other regulatory genes (esp. transcription factors) by the same method should lead to drastic changes in the GRNs. The consequence of destabilization may thus be in long-term development as postulated by the theory of canalization. Flies with modest miRNA reductions may gradually deviate from the developmental norm, resulting in late-stage failures such as shortened longevity. In the optimal culture condition, the survival to adulthood is indeed normal in the dcr-1 KD line but, importantly, adult longevity is reduced by ∼90%. When flies are stressed by high temperature, dcr-1 KD induces lethality earlier in late pupation and, as the perturbations are shifted earlier, the affected stages are shifted correspondingly. Hence, in late stages of development with deviations piling up, GRN would be increasingly in need of stabilization. In conclusion, miRNAs appear to be a solution to weak but constant environmental perturbations.

Open-Nanogap-Induced Strong Electromagnetic Enhancement in Au/AgAu Monolayer as a Stable and Uniform SERS Substrate for Ultrasensitive Detection.

Nanogap-based plasmonic metal nanocrystals have been applied in surface-enhanced Raman scattering detection, while the closed and insufficient electromagnetic fields as well as the nonreproducible Raman signal of the substrate greatly restrict the actual application. Herein, a highly uniform Au/AgAu monolayer with abundant nanogaps and huge electromagnetic enhancement is prepared, which shows ultrasensitive and reproducible SERS detection. Au/AgAu with an inner nanogap is first prepared based on Au nanotriangles, and the nanogap is opened from the three tips via a subsequent etching process. The open-gap Au/AgAu displays much higher SERS efficiency than Au and Au/AgAu with an inner nanogap on detecting crystal violet due to the open-gap induced electromagnetic enhancement and improved molecular absorption. Furthermore, the open-gap Au/AgAu monolayer is prepared via interfacial self-assembly, which shows further improved SERS due to the dense and strong hotspots in the nanocavities induced by the electromagnetic coupling between adjacent open gaps. The monolayer possesses excellent signal stability, uniformity, and reproducibility. The analytic enhancement factor and relative standard deviation reach to 2.12 × 108 and 4.65% on detecting crystal violet, respectively. Moreover, the monolayer achieves efficient detection of thiram in apple juice, biphenyl-4-thiol, 4-mercaptobenzoic, melamine, and a mixed solution of four different molecules, showing great promise in practical detection.

High accuracy ranging for space debris with spaceborne single photon Lidar.

The increasing risk posed by space debris highlights the need for accurate localization techniques. Spaceborne single photon Lidar (SSPL) offers a promising solution, overcoming the limitations of traditional ground-based systems by providing expansive coverage and superior maneuverability without being hindered by weather, time, or geographic constraints. This study introduces a novel approach leveraging non-parametric Bayesian inference and the Dirichlet process mixture model (DPMM) to accurately determine the distance of space debris in low Earth orbit (LEO), where debris exhibits nonlinear, high dynamic motion characteristics. By integrating extended Kalman filtering (EKF) for range gating, our method captures the temporal distribution of reflected photons, employing Markov chain Monte Carlo (MCMC) for iterative solutions. Experimental outcomes demonstrate our method's superior accuracy over conventional statistical techniques, establishing a clear correlation between radial absolute velocity and ranging error, thus significantly enhancing monostatic space debris localization.

An evaluation of computational methods for aggregate data meta-analyses of diagnostic test accuracy studies.

BACKGROUND: A Generalized Linear Mixed Model (GLMM) is recommended to meta-analyze diagnostic test accuracy studies (DTAs) based on aggregate or individual participant data. Since a GLMM does not have a closed-form likelihood function or parameter solutions, computational methods are conventionally used to approximate the likelihoods and obtain parameter estimates. The most commonly used computational methods are the Iteratively Reweighted Least Squares (IRLS), the Laplace approximation (LA), and the Adaptive Gauss-Hermite quadrature (AGHQ). Despite being widely used, it has not been clear how these computational methods compare and perform in the context of an aggregate data meta-analysis (ADMA) of DTAs. METHODS: We compared and evaluated the performance of three commonly used computational methods for GLMM - the IRLS, the LA, and the AGHQ, via a comprehensive simulation study and real-life data examples, in the context of an ADMA of DTAs. By varying several parameters in our simulations, we assessed the performance of the three methods in terms of bias, root mean squared error, confidence interval (CI) width, coverage of the 95% CI, convergence rate, and computational speed. RESULTS: For most of the scenarios, especially when the meta-analytic data were not sparse (i.e., there were no or negligible studies with perfect diagnosis), the three computational methods were comparable for the estimation of sensitivity and specificity. However, the LA had the largest bias and root mean squared error for pooled sensitivity and specificity when the meta-analytic data were sparse. Moreover, the AGHQ took a longer computational time to converge relative to the other two methods, although it had the best convergence rate. CONCLUSIONS: We recommend practitioners and researchers carefully choose an appropriate computational algorithm when fitting a GLMM to an ADMA of DTAs. We do not recommend the LA for sparse meta-analytic data sets. However, either the AGHQ or the IRLS can be used regardless of the characteristics of the meta-analytic data.

Preparation of a Nanosheeted Uranyl-Organic Framework for Enhanced Photocatalytic Oxidation of Toluene.

Preparation of ultrathin metal-organic framework (MOF) nanosheets is an effective way to improve the catalytic efficiency of MOF photocatalysts owing to their superiority in reducing the recombination rate of photogenerated electrons and holes and enhancing charge transfer. Herein, a light-sensitive two-dimensional uranyl-organic framework named HNU-68 was synthesized. Due to its interlayer stacking structure, the corresponding ultrathin nanosheets with a thickness of 4.4 nm (HNU-68-N) can be obtained through ultrasonic exfoliation. HNU-68-N exhibited an enhanced ability to selectively oxidize toluene to benzaldehyde, with the value of turnover frequency being approximately three times higher than that of the bulk HNU-68. This enhancement is attributed to the smaller size and interface resistance of the layered HNU-68-N nanosheets, which facilitate more thorough substrate contact and faster charge transfer, leading to an improvement in the photocatalytic efficiency. This work provides a potential candidate for the application of ultrathin uranyl-based nanosheets.

Schizophrenia and risk preference: a bidirectional two-sample mendelian randomization study.

Increasing evidence shows that risk preference is associated with schizophrenia. However, the causality and direction of this association are not clear; Therefore, we used Mendelian randomization (MR) to examine the potential bidirectional relationship between risk preference and schizophrenia. Genome-wide association studies (GWAS) summary data on risk preference of 939,908 participants from the UK Biobank and 23andMe were used to identify general risk preference. Data from 320,404 subjects (76,755 cases and 243,649 controls) from The Psychiatric Genomics Consortium were used to identify schizophrenia. The weighted median (WM), the inverse variance weighted (IVW), and the Mendelian randomization-Egger (MR-Egger) methods were used for the MR analysis to estimate the causal effect and detect the directional pleiotropy. The GWAS summary data were respectively from two combined samples, containing 939,908 and 320,404 subjects of European ancestry. Mendelian randomization evidence suggested that risk preference was associated with increased onset of schizophrenia (OR = 2.84, 95CI%: 1.77-4.56, P = 1.58*10 - 5) and that schizophrenia was also associated with raised risk preference (OR = 1.11, 95CI%: 1.07-1.15, P = 7.98*10 - 8). With the use of large-scale GWAS data, robust evidence suggests an interaction between risk preference and schizophrenia. This also indicates that early identification of and intervention for increased risk preference may improve the prognosis of schizophrenia.

Effects of elevated remnant cholesterol on outcomes of acute ischemic stroke patients receiving mechanical thrombectomy.

OBJECTIVE: Large cohort studies provided evidence that elevated remnant cholesterol (RC) was an important risk factor for ischemic stroke. However, the association between high RC and clinical outcomes in acute ischemic stroke (AIS) individuals was still undetermined. METHODS: This retrospective study enrolled 165 AIS patients undergoing mechanical thrombectomy in one tertiary stroke center. We divided patients into two groups based on the median of their RC levels (0.49 mmol/L). The modified Rankin Scale (mRS) was used to evaluate the primary outcome 90 days after the onset of symptoms. The mRS scores ≤ 2 and ≤ 1 at 90 days were deemed as favorable and excellent outcomes, respectively. RESULTS: In the overall AIS patients undergoing mechanical thrombectomy, there was no obvious distinction between the high and low RC group at 90-day favorable outcome (41.0% vs. 47.1%, P = 0.431) or excellent outcome (23.1% vs. 31.0%, P = 0.252). In the subgroup analysis stratified by stroke etiology, non-large artery atherosclerosis (non-LAA) stroke patients yielded with less favorable or excellent prognosis in the high RC group (26.8% vs. 46.8%, adjusted OR = 0.31, 95%CI: 0.11-0.85, P = 0.023; or 12.2% vs. 29.0%, adjusted OR = 0.18, 95%CI: 0.04-0.80, P = 0.024, respectively.). Post hoc power analyses indicated that the power was sufficient for favorable outcome (80.38%) and excellent outcome (88.72%) in non-LAA stroke patients. Additionally, RC can enhance the risk prediction value of a poor outcome (mRS scores 3-6) based on traditional risk indicators (including age, initial NIHSS score, operative duration, and neutrophil-to-lymphocyte ratio) for non-LAA stroke patients (AUC = 0.86, 95%CI: 0.79-0.94, P < 0.001). CONCLUSION: In AIS patients undergoing mechanical thrombectomy, elevated RC was independently related to poor outcome for non-LAA stroke patients, but not to short-term prognosis of LAA stroke patients.

Myth behind Metastable and Stable n-Hexylammonium Bromide-Based Low-Dimensional Perovskites.

In perovskite solar cells, passivating the surface or interface that contains a high concentration of defects, specifically deep-level defects, is one of the most important topics to substantially enhance the power conversion efficiency and stability of the devices. Long-chain alkylammonium bromides have been widely and commonly adapted for passivation treatment. However, the mechanism behind is still not well explored as the formation route and the exact structure of these alkylammonium bromide-based low-dimensional perovskites are unclear. Herein, we investigate the physical and chemical properties of an n-hexylammonium bromide (HABr)-based low-dimensional perovskite including both thin films and single crystals. First of all, the HA2PbBr4 perovskite film and aged single crystal demonstrate different X-ray diffraction patterns from those of the fresh as-prepared single crystal. We found that the fresh HA2PbBr4 single crystal exhibits a metastable phase as its structure changes with aging due to the relaxation of crystal lattice strains, whereas the HA2PbBr4 perovskite film is pretty stable as the aged single crystal. Upon reacting with FAPbI3, HABr can be intercalated into the FAPbI3 lattice to form a mixed-cation perovskite of HAFAPbI3Br, which is in a dynamic equilibrium of decomposition and formation. In contrast, the reaction of HABr with excess PbI2 forms a stable HA2PbI2Br2 perovskite. Based on such findings, we rationally develop a HA2PbI2Br2-passivated FACs-based perovskite by reacting HABr with excess PbI2, the photovoltaics based on which are more stable and efficient than those passivated by the HAFAPbI3Br perovskite. Our discovery paves way for a more in-depth study of bromide-containing low-dimensional perovskites and their optoelectronic applications.

Metagenomic sequencing reveals altered gut microbial compositions and gene functions in patients with non-segmental vitiligo.

BACKGROUND: Vitiligo has been correlated with an abnormal gut microbiota. We aimed to systematically identify characteristics of the gut microbial compositions, genetic functions, and potential metabolic features in patients with non-segmental vitiligo. METHODS: Twenty-five patients with non-segmental vitiligo and 25 matched healthy controls (HCs) were enrolled. Metagenomic sequencing and bioinformatic analysis were performed to determine the gut microbiota profiles. Differences in gut microbiota diversity and composition between patients with vitiligo and HCs were analyzed. Gene functions and gut metabolic modules were predicted with the Kyoto Encyclopedia of Gene and Genomes (KEGG) and MetaCyc databases. RESULTS: Compared with HCs, alpha diversity of intestinal microbiome in vitiligo patients was significantly reduced. At the species level, the relative abundance of Staphylococcus thermophiles was decreased, and that of Bacteroides fragilis was increased in patients with vitiligo compared with those of the HCs. Linear discriminant analysis (LDA) effect size (LEfSe) analysis revealed representative microbial markers of Lachnospiraceae_bacterium_BX3, Massilioclostridium_coli, TM7_phylum_sp_oral_taxon_348 and Bacteroides_fragilis for patients with vitiligo. KEGG gene function analysis showed that the NOD-like receptor signaling pathway was significantly enriched in patients with vitiligo. Gut metabolic modules (GMMs) analysis showed that cysteine degradation was significantly down-regulated, and galactose degradation was up-regulated in patients with vitiligo. A panel of 28 microbial features was constructed to distinguish patients with vitiligo from HCs. CONCLUSIONS: The gut microbial profiles and genetic functions of patients with vitiligo were distinct from those of the HCs. The identified gut microbial markers may potentially be used for earlier diagnosis and treatment targets.

Directional Damping of Plasmons at Metal-Semiconductor Interfaces.

ConspectusOver the past decade, it has been shown that surface plasmons can enhance photoelectric conversion in photovoltaics, photocatalysis, and other optoelectronic applications through their plasmonic absorption and damping processes. However, plasmonically enhanced devices have yet to routinely match or exceed the efficiencies of traditional semiconductor devices. The effect of plasmonic losses dissipates the absorbed photoenergy mostly into heat and that has hampered the realization of superior next-generation plasmonic optoelectronic devices. Several approaches are being explored to alleviate this situation, including using gain to compensate for the plasmonic losses, designing and synthesizing alternative low-loss plasmonic materials, and reducing activation barriers in plasmonic devices and physical thicknesses of photoabsorber layers to lower the plasmonic losses. A newly proposed plasmon-induced interfacial charge-transfer transition (PIICTT) mechanism has proven to be effective in minimizing energy loss during interfacial charge transfer. The PIICTT leads to a damping of metallic plasmonics by directly generating excitons at the plasmonic metal/semiconductor heteronanostructures. This novel concept has been proven to overcome some of the limitations of electron-transfer inefficiencies, renewing a focus on surface plasmon damping processes with the goal that the plasmonic excitation energies of metal nanoparticles can be more efficiently transferred to the adjacent semiconductor components in the absence and presence of an effective interlayer of carrier-selective blocking layer (CSBL). Several theoretical and experimental studies have concluded that efficient plasmon-induced ultrafast hot-carrier transfer was observed in plasmonic-metal/semiconductor heteronanostructures. The PIICTT mechanism may well be a general phenomenon at plasmonic metal/semiconductor, metal/molecule, semiconductor/semiconductor, and semiconductor/molecule heterointerfaces. Thus, the PIICTT presents a new opportunity to limit energy loss in plasmonic-metal nanostructures and increase device efficiencies based on plasmonic coupling. The nonradiative damping of surface plasmons can impact the energy flux direction and thereby provide a new process beyond light trapping, focusing, and hot carrier creation.In this Account, we draw much attention to the benefits of interfacial plasmonic coupling, highlighting recent pioneering discoveries in which plasmon-induced interfacial charge- and energy-transfer processes enable the generation of hot charge carriers near the plasmonic-metal/semiconductor interfaces. This process is likely to increase the photoelectric conversion efficiency, constituting "plasmonic enhancement". We also discuss recent advances in the dynamics of surface plasmon relaxation and highlight exciting new possibilities for plasmonic metals and their interactions with strongly attached semiconductors to provide directional energy fluxes. While this new research area comes on the heels of much elaborate research on both metal and semiconductor nanomaterials, it provides a subtle but important refinement in understanding the optoelectronic properties of materials with far-reaching consequences from fundamental interface science to technological applications. We hope that this Account will contribute to a more systematic description of interface-coupled plasmonics, both fundamentally and in terms of applications toward the design of plasmonic heterostructured devices.

Ranging analysis of a moving target based on the dynamic instrument response function.

A ranging high-speed moving target with a high accuracy is challenging for a single-photon ranging system (SPRS). In this Letter, the dynamic instrument response function (IRF) is proposed to establish a dynamic discrete model (DDM) by introducing a velocity and a system timing resolution, which leads to better accuracy of cross-correlation results. And with the data of a dynamic Monte Carlo (DMC), the ranging accuracy can be improved with DDM.

Optimized electromagnetic enhancement and charge transfer in MXene/Au/Cu2O hybrids for achieving efficient SERS.

The rational optimization of the electromagnetic field enhancement and charge transfer in a Raman substrate is vital for achieving efficient surface-enhanced Raman scattering (SERS). Herein, a ternary plasmonic substrate, whose structure-adjustable Au nanotriangle/Cu2O hybrids are combined with two-dimensional Ti3C2Tx MXene ultrathin nanosheets, is prepared and used for efficient SERS detection of molecules. By controlling the growth of Cu2O on Au nanotriangles, Au/Cu2O hybrids with three tips exposed are prepared, which show much better SERS performance than bare Au and core-shell Au@Cu2O in detecting methylene blue (MB) under excitation at 785 nm due to the optimized electromagnetic field enhancement and charge transfer. Furthermore, the Au/Cu2O hybrids are transferred to the plasmonic Ti3C2Tx nanosheet, generating a further enhanced electromagnetic field around their interfaces. As a result, the MXene/Au/Cu2O hybrids present further improved SERS activity, and their analytical enhancement factor reaches 2.4 × 109 and the detection limit is as low as 10-12 M. The enhancement mechanism can be ascribed to the improved electric field enhancement around the Au tips and the interface between MXene and Au/Cu2O. Meanwhile, the multiple charge-transfer processes between Au, Cu2O, MXene, and MB also play an important role in improving the SERS signal.

An inducible Komagataella phaffii system for protein expression using sorbitol dehydrogenase promoter.

OBJECTIVES: The aim of the present work was to develop a methanol-independent Komagataella phaffii (K. phaffii) strain using a non-methanol promoter. RESULTS: In this study, the food grade enzyme xylanase from Aspergillus niger ATCC 1015 was used as the reporter protein, a recombinant K. phaffii containing a cascade gene circus was designed and constructed using sorbitol as inducer. Sorbitol induced PSDH leading to MIT1 expression firstly, and heterologous protein xylanase expression finally. This system showed 1.7 fold of xylanase activity at the condition of single copy number of extra MIT1, and 2.1 fold of xylanase activity at condition of multi-copy extra MIT1 gene. CONCLUSIONS: This sorbitol-induced expression system of K. phaffii avoided toxic and explosive methanol. It was a novel cascade gene expression and a food safety system.

Multi-Sensor Data Fusion and CNN-LSTM Model for Human Activity Recognition System.

Human activity recognition (HAR) is becoming increasingly important, especially with the growing number of elderly people living at home. However, most sensors, such as cameras, do not perform well in low-light environments. To address this issue, we designed a HAR system that combines a camera and a millimeter wave radar, taking advantage of each sensor and a fusion algorithm to distinguish between confusing human activities and to improve accuracy in low-light settings. To extract the spatial and temporal features contained in the multisensor fusion data, we designed an improved CNN-LSTM model. In addition, three data fusion algorithms were studied and investigated. Compared to camera data in low-light environments, the fusion data significantly improved the HAR accuracy by at least 26.68%, 19.87%, and 21.92% under the data level fusion algorithm, feature level fusion algorithm, and decision level fusion algorithm, respectively. Moreover, the data level fusion algorithm also resulted in a reduction of the best misclassification rate to 2%~6%. These findings suggest that the proposed system has the potential to enhance the accuracy of HAR in low-light environments and to decrease human activity misclassification rates.

Near-Space Wide-Area and High-Resolution Imaging System Design and Implementation.

The near-space atmosphere is thin, and the atmospheric refraction and scattering on optical observation is very small, making it very suitable for wide-area and high-resolution surveillance using high-altitude balloon platforms. This paper adopts a 9344 × 7000 CMOS sensor to obtain high-resolution images, generating large-field-of-view imaging through the swing scanning of the photoelectric sphere and image stitching. In addition, a zoom lens is designed to achieve flexible applications for different scenarios, such as large-field-of-view and high-resolution imaging. The optical design results show that the camera system has good imaging quality within the focal length range of 320 mm-106.7 mm, and the relative distortion values at different focal lengths are less than 2%. The flight results indicate that the system can achieve seamless image stitching at a resolution of 0.2 m@20 km and the imaging field of view angle exceeds 33°. This system will perform other near-space flight experiments to verify its ultra-wide (field of view exceeding 100°) high-resolution imaging application.

Surface Termination on Unstable Methylammonium-based Perovskite Using a Steric Barrier for Improved Perovskite Solar Cells.

Compared to widely adopted low-dimensional/three-dimensional (LD/3D) heterostructure, functional organic cation based surface termination on perovskite can not only realize advantage of defect passivation but also prevent potential disadvantage of the heterostructure induced intercalation into 3D perovskite. However, it is still very challenging to controllably construct surface termination on organic-inorganic hybrid perovskite because the functional organic cations' substitution reaction is easy to form LD/3D heterostructure. Here, we report using a novel benzyltrimethylammonium (BTA) functional cation with rational designed steric hindrance to effectively surface terminate onto methylammonium lead triiodide (MAPbI3 ) perovskite, which is composed of the most unstable MA cations. The BTA cation is difficult to form a specific 1.5-dimensional perovskite of BTA4 Pb3 I10 by cation substitution with MA cation, which then provides a wide processing window (around 10 minutes) for surface terminating on MAPbI3 films. Moreover, the BTAI surface terminated BTAI-MAPbI3 shows better passivation effect than BTA4 Pb3 I10 -MAPbI3 heterojunction. Finally, BTAI surface terminated solar cell (0.085 cm2 ) and mini-module (11.52 cm2 ) obtained the efficiencies of 22.03 % and 18.57 %, which are among the highest efficiencies for MAPbI3 based ones.

Run or Die in the Evolution of New MicroRNAs-Testing the Red Queen Hypothesis on De Novo New Genes.

The Red Queen hypothesis depicts evolution as the continual struggle to adapt. According to this hypothesis, new genes, especially those originating from nongenic sequences (i.e., de novo genes), are eliminated unless they evolve continually in adaptation to a changing environment. Here, we analyze two Drosophila de novo miRNAs that are expressed in a testis-specific manner with very high rates of evolution in their DNA sequence. We knocked out these miRNAs in two sibling species and investigated their contributions to different fitness components. We observed that the fitness contributions of miR-975 in Drosophila simulans seem positive, in contrast to its neutral contributions in D. melanogaster, whereas miR-983 appears to have negative contributions in both species, as the fitness of the knockout mutant increases. As predicted by the Red Queen hypothesis, the fitness difference of these de novo miRNAs indicates their different fates.

Deconvolution of expression for nascent RNA-sequencing data (DENR) highlights pre-RNA isoform diversity in human cells.

MOTIVATION: Quantification of isoform abundance has been extensively studied at the mature RNA level using RNA-seq but not at the level of precursor RNAs using nascent RNA sequencing. RESULTS: We address this problem with a new computational method called Deconvolution of Expression for Nascent RNA-sequencing data (DENR), which models nascent RNA-sequencing read-counts as a mixture of user-provided isoforms. The baseline algorithm is enhanced by machine-learning predictions of active transcription start sites and an adjustment for the typical 'shape profile' of read-counts along a transcription unit. We show that DENR outperforms simple read-count-based methods for estimating gene and isoform abundances, and that transcription of multiple pre-RNA isoforms per gene is widespread, with frequent differences between cell types. In addition, we provide evidence that a majority of human isoform diversity derives from primary transcription rather than from post-transcriptional processes. AVAILABILITY AND IMPLEMENTATION: DENR and nascentRNASim are freely available at https://github.com/CshlSiepelLab/DENR (version v1.0.0) and https://github.com/CshlSiepelLab/nascentRNASim (version v0.3.0). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.