Downstream Core Research Articles

From promoter motif to cardiac function: a single DPE motif affects transcription regulation and organ function in vivo.

Transcription initiates at the core promoter, which contains distinct core promoter elements. Here, we highlight the complexity of transcriptional regulation by outlining the effect of core promoter-dependent regulation on embryonic development and the proper function of an organism. We demonstrate in vivo the importance of the downstream core promoter element (DPE) in complex heart formation in Drosophila. Pioneering a novel approach using both CRISPR and nascent transcriptomics, we show the effects of mutating a single core promoter element within the natural context. Specifically, we targeted the downstream core promoter element (DPE) of the endogenous tin gene, encoding the Tinman transcription factor, a homologue of human NKX2-5 associated with congenital heart diseases. The 7 bp substitution mutation results in massive perturbation of the Tinman regulatory network that orchestrates dorsal musculature, which is manifested as physiological and anatomical changes in the cardiac system, impaired specific activity features, and significantly compromised viability of adult flies. Thus, a single motif can have a critical impact on embryogenesis and, in the case of DPE, functional heart formation.

Time-varying microplastic contributions of a large urban and industrial area to river sediments

The quantification of microplastic (MP) pollution in rivers is often constrained by a lack of historical data on a multi-decadal scale, which hinders the evaluation of public policies. In this study, MP contents and trends were analyzed in dated sediment cores sampled upstream and downstream of a large metropolis, in environmental deposits that exhibited consistent sedimentation patterns from the 1980s to 2021. After a thorough sedimentological analysis, MPs were quantified in samples by micro Fourier Transform InfraRed spectroscopy (μFTIR imaging) and a density separation and organic matter digestion procedure. Microplastics recorded in the upstream core are relatively ubiquitous all along the dated sequence. The results also confirmed a sever increase of microplastics levels in the downstream core, by one order of magnitude, and an increase of polymer types. Polypropylene, polyethylene, and polystyrene represent ubiquitous contamination and were predominant at the two stations, whereas polyvinyl chloride and polytetrafluoroethylene were suspected to be abundant at the downstream station, but were not detected at the upstream station. Their presence could be linked to local contamination from specific industrial sources that manufactured and utilized these polymers. Surprisingly, in the downstream station sediment has recorded a relative improvement in polymers associated with industrial sources since the 2000s and, to a lesser extent, for ubiquitous ones since the 2010s. This trend of mitigation diverges from that of global assessments, that assume uncontrolled MP pollution, and suggest that European Union wastewater policy and regulation on industrial discharges have positively influenced water quality, and certainly also on MPs. However, the accumulation of microplastics remains high in recent deposits and raises the emerging concern of the long-term management of these reservoirs.

Overtopping Failure Process and Core Wall Fracture Mechanism of a New Concrete Core Wall Dam

Concrete core wall dams have emerged as a cost-effective alternative to the reconstruction of old dams. However, the flooding mechanism and flood line of these dams differ significantly from traditional earth and rockfill dams due to the concrete core wall functioning as reinforcement. This study presents model tests that simulate the overtopping failure of earth and rockfill dams with concrete core walls of various thicknesses. The hydrologic curve and two-dimensional evolution of the breach are analyzed, and mechanical analysis examines the relationship between core wall thickness and free face during core wall failure. Results indicate that the presence of the concrete core wall shifts the overtopping failure mode to the scour pit failure mode. The scour pit failure mode occurs when upstream water scours the downstream core wall to form scour holes and free faces. Continuous scouring increases the depth of the free face, ultimately causing the moment between the two sides of the core wall to exceed the bending moment of the core wall, resulting in fracture. The study provides a theoretical basis for the design of core walls for this new type of dam.

The Hippo pathway in endometrial cancer: a potential therapeutic target?

Endometrial cancer, one of the most prevalent malignant cancers tumors of the female reproductive tract, has been increasing in incidence and mortality rates around the world. The Hippo pathway, one of the eight traditional human cancer signaling pathways, is an intricate signaling network that regulates cell proliferation, differentiation, and migration as well as restricting organ size in response to a range of intracellular and extracellular signals. Inhibiting the Hippo pathway results in aberrant activation of its downstream core component YAP/TAZ, which can enhance cancer cells’ metabolism and maintain their stemness. Additionally, the Hippo pathway can modulate the tumor microenvironment and induce drug resistance, where tumorigenesis and tumor progression occur. However, the Hippo pathway has been little researched in endometrial cancer. Here, we aim to review how the Hippo pathway contributes to the onset, development and the potential treatment of endometrial cancer with the aim of providing new therapeutic targets.

Energy Repartition and Entropy Generation across the Earth’s Bow Shock: MMS Observations

The evolution of plasma entropy and the process of plasma energy redistribution at the collisionless plasma shock front are evaluated based on the high temporal resolution data from the four Magnetospheric Multiscale spacecraft during the crossing of the terrestrial bow shock. The ion distribution function has been separated into the populations with different characteristic behaviors in the vicinity of the shock: the upstream core population, the reflected ions, the gyrating ions, the ions trapped in the vicinity of the shock, and the downstream core population. The values of ion and electron moments (density, bulk velocity, and temperature) have been determined separately for these populations. It is shown that the solar wind core population bulk velocity slows down mainly in the ramp with the electrostatic potential increase but not in the foot region as it was supposed. The reflected ion population determines the foot region properties, so the proton temperature peak in the foot region is an effect of the relative motion of the different ion populations, rather than an actual increase in the thermal speed of any of the ion population. The ion entropy evaluated showed a significant increase across the shock: the enhancement of the ion entropy occurs in the foot of the shock front and at the ramp, where the reflected ions are emerging in addition to the upstream solar wind ions, the anisotropy growing to generate the bursts of ion-scale electrostatic waves. The entropy of electrons across the shock does not show a significant change: electron heating goes almost adiabatically.

Drug Discovery for Periodontitis Treatment Based on Big Data Mining, Systems Biology, and Deep Learning Methods

Periodontitis, a chronic inflammatory oral condition triggered by bacteria, archaea, viruses, and eukaryotic organisms, is a well-known and widespread disease around the world. While there are effective treatments for periodontitis, there are also several shortcomings associated with its management, including limited treatment options, the risk of recurrence, and the high cost of treatment. Our goal is to develop a more efficient, systematic drug design for periodontitis before clinical trials. We work on systems drug discovery and design for periodontitis treatment via systems biology and deep learning methods. We first applied big database mining to build a candidate genome-wide genetic and epigenetic network (GWGEN), which includes a protein-protein interaction network (PPIN) and a gene regulatory network (GRN) for periodontitis and healthy control. Next, based on the unhealthy and healthy microarray data, we applied system identification and system order detection methods to remove false positives in candidate GWGENs to obtain real GWGENs for periodontitis and healthy control, respectively. After the real GWGENs were obtained, we picked out the core GWGENs based on how significant the proteins and genes were via the principal network projection (PNP) method. Finally, referring to the annotation of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we built up the core signaling pathways of periodontitis and healthy control. Consequently, we investigated the pathogenic mechanism of periodontitis by comparing their core signaling pathways. By checking up on the downstream core signaling pathway and the corresponding cellular dysfunctions of periodontitis, we identified the fos proto-oncogene, AP-1 Transcription Factor Subunit (FOS), TSC Complex Subunit 2 (TSC2), Forkhead Box O1 (FOXO1), and nuclear factor kappa-light chain enhancer of activated B cells (NF-κB) as significant biomarkers on which we could find candidate molecular drugs to target. To achieve our ultimate goal of designing a combination of molecular drugs for periodontitis treatment, a deep neural network (DNN)-based drug-target interaction (DTI) model was employed. The model is trained with the existing drug-target interaction databases for the prediction of candidate molecular drugs for significant biomarkers. Finally, we filter out brucine, disulfiram, verapamil, and PK-11195 as potential molecular drugs to be combined as a multiple-molecular drug to target the significant biomarkers based on drug design specifications, i.e., adequate drug regulation ability, high sensitivity, and low toxicity. In conclusion, we investigated the pathogenic mechanism of periodontitis by leveraging systems biology methods and thoroughly developed a therapeutic option for periodontitis treatment via the prediction of a DNN-based DTI model and drug design specifications.

Numerical study on prediction and discrimination methods of propeller tip vortex cavitation inception

Tip vortex cavitation is typically the first type of cavitation in real ship propellers due to the scale effect. To lessen or eliminate propeller cavitation noise, it is necessary to effectively identify and predict the tip vortex cavitation initiation of the propeller and run the propeller as far as possible in the “non-cavitation area.” However, for the current numerical computation, it is impossible to determine the minimum pressure at the vortex core directly and correctly, making it difficult to anticipate the cavitation initiation of the propeller tip vortex. In this paper, based on computational fluid dynamics (CFD) numerical calculations and the tip vortex model proposed by Xin [Proceedings of 2013 Ship Hydrodynamics Conference (2013), pp. 211–218], we propose a new prediction method for propeller tip vortex cavitation initiation—“the tip vortex model method.” The propeller tip vortex is solved by CFD calculation in this model, and the minimum pressure at the downstream vortex core is examined based on the tip vortex model to determine the initiation of propeller cavitation. We examine the cavitation inception using the tip vortex model method and compare it to the results obtained using the minimum pressure coefficient method and the minimum vapor volume method. It is discovered that the cavitation inception number obtained by the tip vortex model method is closer to the experimental results. Furthermore, the effects of different turbulence models and grid settings on the prediction of tip vortex cavitation initiation are investigated, providing an effective reference for the prediction of propeller tip vortex cavitation initiation.

Analysis of the Drosophila and human DPR elements reveals a distinct human variant whose specificity can be enhanced by machine learning.

The RNA polymerase II core promoter is the site of convergence of the signals that lead to the initiation of transcription. Here, we performed a comparative analysis of the downstream core promoter region (DPR) in Drosophila and humans by using machine learning. These studies revealed a distinct human-specific version of the DPR and led to the use of machine learning models for the identification of synthetic extreme DPR motifs with specificity for human transcription factors relative to Drosophila factors and vice versa. More generally, machine learning models could similarly be used to design synthetic DNA elements with customized functional properties.

Molecular biology of the cell

Molecular biology of the cell

Composition of deposited sediment and its temporal variation in a disturbed tropical catchment in the Kelantan river basin, Peninsular Malaysia.

Pristine tropical river systems are coming under increasing pressure from the development of economic resources such as forestry and mining for valuable elements. The Lebir catchment, north eastern Malaysia, is now under development as a result of unregulated tree felling and mining for essential and rare metals. Two sediment cores, one in the upstream reaches and the other from the downstream reaches, were taken from flood prone area of the Lebir River, Malaysia, and analysed for their elemental composition by XRF, specifically Al, Si, Fe, Ca, K, Mg, Mn, V, Cu, Ni, Pb, Cr, Zn, As, Th and U. Activities of fallout radionuclides, 137Cs and 210Pb were also determined to from a geochronological context. The elemental concentrations in the soils were assessed in terms of their enrichment factor and Si, Ca, K, Mg, Mn, V, Cu, Ni and Zn were found not to be enriched, whereas As, Th and U had elevated enrichment factors. The Th and U were particularly enriched in the downstream core indicating inputs from a tributary that drains a catchment with known deposits of Th and possibly U. The results suggest that the growth in economic development is fostering the transport of contaminants by the major rivers which, in turn, is contaminating the riverine floodplains. This points to the need for a more integrated and holistic approach to river basin management to maintain the environmental quality of these fragile aquatic systems.

Experimental and numerical study of heat transfer and pressure loss in a multi-convergent swirl tube with tangential jets

This paper presents a comparative experimental and numerical study of heat transfer and pressure loss in a swirl cooling system with multi-convergent tubes. The results are compared with those of a baseline circular swirl tube. The two swirl tubes are both with multiple tangential jet slots, which can induce large-scale swirling flows and significantly enhance the convective heat transfer. The multi-convergent swirl tube can be considered as an effective internal cooling method for the gas turbine blade leading edge. Transient liquid crystal thermography is used to obtain detailed heat transfer distributions on the internal surfaces of the two swirl tubes. It is shown that through a small change in the swirl tube structure the heat transfer rates and uniformity could be significantly improved in the multi-convergent swirl tube. In more detail, the heat transfer of the multi-convergent swirl tube reaches peak values under the jet slots, and then decays more slowly than the baseline swirl tube. After the third jet, the heat transfer of the convergent sections between the inlet jets keep almost stable along the axial direction, since the convergent structures restrain the decay of swirl intensity. Besides, the multi-convergent structure offers a swirl tube with the ability to better resist against the cross flow, which guides the upstream swirling flow to the downstream tube core, avoiding the collision and mixing between the cross flow and the downstream wall jet flow, thus improving the heat transfer rates. Compared with the baseline swirl tube, the experimental globally averaged Nusselt numbers of the multi-convergent swirl tube can be increased by 11.8%-23.3% for the Reynolds number range of 10,000 to 40,000. As a supplement to the experiments, three-dimensional numerical computations provide more insights into the turbulent flow structure in the two kinds of swirl tubes.

The Order Financing Risk Evaluation under the Financial Supply Chain Model Based on the Logistic Model

Order financing, as an innovative business in the financial supply chain model of banks and other financial institutions, has served more and more small and medium‐sized enterprises in recent years, and has also brought new profit points to the financial and logistics industries. Businesses urgently need to carry out relevant risk evaluation research on the risks brought by banks and other financial institutions. Based on this background, this article has carried out relevant research on the construction and evaluation method of the risk evaluation index system of order financing business. Through project research and literature review, the research on the risk evaluation theory and method of order financing carried out by banks and other financial institutions is not perfect. The role‐played in order financing and the key risk variables faced by financial institutions, and innovatively proposed an evaluation method based on the logistics model. Based on the analysis of order financing risk factors, and through literature review and expert interviews, an evaluation index system initially constructed from five aspects: financing companies, downstream core companies, logistics companies, supply chain operations and external environment. Through questionnaire surveys and statistical analysis of the survey results, a complete, qualitied the risk evaluation index system for order financing business was finally determined. Taking the order‐financing project jointly carried out by commercial banks and logistics companies as an example.

CIRBP-OGFR axis safeguards against cardiomyocyte apoptosis and cardiotoxicity induced by chemotherapy

Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.

3D analysis of the 174-m high Quxue asphalt-core rockfill dam in a narrow canyon

The site for the high Quxue Dam has a narrow canyon with very steep abutments and complex geology in Sichuan Province, China. Various types of embankment and concrete dams were considered and an asphalt-core embankment dam (ACED), 174 m high, was selected. The asphalt core is a slender impervious element in an embankment dam and some concerns have been raised about the reliability and safety of the asphalt-core type of dams (ACEDs). This paper presents the case study of the highest asphalt core dam ever built and presents measured and numerical analyses of the core deformations. A 3D non-linear FE analysis has been performed for the Quxue Dam, and the results have been compared with those computed by a 2D analysis to study the effects of the narrow canyon. The computed results are compared with the monitoring data from dam construction and first impoundment. The maximum settlement measured inside the embankment during construction was only about 0.7 m due to the good basaltic rockfill used and the heavy compaction in layers of only 1.0 – 1.2 m thickness. The results of the 3D analysis agree well with the measured downstream displacements and the deflected shape of the thin asphalt core during impoundment, while the 2D analysis overpredicted the maximum displacement by a factor of about two. At a reservoir level 3 m below full supply level, the maximum measured downstream core displacement was only about 80 mm due to the stiff rockfill and the restraining effects of the abutments in the narrow valley.The rockfill behaviour was modelled by the constitutive relationship proposed by Duncan and Chang (1970). The rockfill parameters were determined by laboratory tests prior to construction and were adjusted to better match field observations of vertical settlements during construction. As asphalt concrete exhibits pronounced visco-elastoplastic behaviour, the material modelling was based on long-term triaxial creep tests on samples drilled out of the dam core. The performance monitoring and numerical analysis results for the record-high Quxue ACED document that the concerns expressed about the asphalt core safety and behaviour is not warranted. The asphalt core type of dam is suitable even for high ACEDs in narrow valleys with steep abutments.

Chemogenetic suppression of macaque V4 neurons produces retinotopically specific deficits in downstream IT neural activity patterns and core object recognition behavior

Chemogenetic suppression of macaque V4 neurons produces retinotopically specific deficits in downstream IT neural activity patterns and core object recognition behavior

The Core Promoter Is a Regulatory Hub for Developmental Gene Expression.

The development of multicellular organisms and the uniqueness of each cell are achieved by distinct transcriptional programs. Multiple processes that regulate gene expression converge at the core promoter region, an 80 bp region that directs accurate transcription initiation by RNA polymerase II (Pol II). In recent years, it has become apparent that the core promoter region is not a passive DNA component, but rather an active regulatory module of transcriptional programs. Distinct core promoter compositions were demonstrated to result in different transcriptional outputs. In this mini-review, we focus on the role of the core promoter, particularly its downstream region, as the regulatory hub for developmental genes. The downstream core promoter element (DPE) was implicated in the control of evolutionarily conserved developmental gene regulatory networks (GRNs) governing body plan in both the anterior-posterior and dorsal-ventral axes. Notably, the composition of the basal transcription machinery is not universal, but rather promoter-dependent, highlighting the importance of specialized transcription complexes and their core promoter target sequences as key hubs that drive embryonic development, differentiation and morphogenesis across metazoan species. The extent of transcriptional activation by a specific enhancer is dependent on its compatibility with the relevant core promoter. The core promoter content also regulates transcription burst size. Overall, while for many years it was thought that the specificity of gene expression is primarily determined by enhancers, it is now clear that the core promoter region comprises an important regulatory module in the intricate networks of developmental gene expression.

Computational identification and experimental characterization of preferred downstream positions in human core promoters.

Metazoan core promoters, which direct the initiation of transcription by RNA polymerase II (Pol II), may contain short sequence motifs termed core promoter elements/motifs (e.g. the TATA box, initiator (Inr) and downstream core promoter element (DPE)), which recruit Pol II via the general transcription machinery. The DPE was discovered and extensively characterized in Drosophila, where it is strictly dependent on both the presence of an Inr and the precise spacing from it. Since the Drosophila DPE is recognized by the human transcription machinery, it is most likely that some human promoters contain a downstream element that is similar, though not necessarily identical, to the Drosophila DPE. However, only a couple of human promoters were shown to contain a functional DPE, and attempts to computationally detect human DPE-containing promoters have mostly been unsuccessful. Using a newly-designed motif discovery strategy based on Expectation-Maximization probabilistic partitioning algorithms, we discovered preferred downstream positions (PDP) in human promoters that resemble the Drosophila DPE. Available chromatin accessibility footprints revealed that Drosophila and human Inr+DPE promoter classes are not only highly structured, but also similar to each other, particularly in the proximal downstream region. Clustering of the corresponding sequence motifs using a neighbor-joining algorithm strongly suggests that canonical Inr+DPE promoters could be common to metazoan species. Using reporter assays we demonstrate the contribution of the identified downstream positions to the function of multiple human promoters. Furthermore, we show that alteration of the spacing between the Inr and PDP by two nucleotides results in reduced promoter activity, suggesting a spacing dependency of the newly discovered human PDP on the Inr. Taken together, our strategy identified novel functional downstream positions within human core promoters, supporting the existence of DPE-like motifs in human promoters.

Flow Characteristics of a Model Can-Type Combustor

Numerical simulations are performed on a can-type combustor in order to indentify various flow features. Elementary flow features like jet-in-crossflow, opposed jets, swirl and recirculation zones are present in a combined form. Momentum flux ratio between axial air flow and radial primary air jets from the circumference of the combustor is an important parameter. While increasing mass flow rate of the radial jet, the jet-in-cross flow structure changes to opposed jet. Swirl of axial jet is favourable for opposed jet configuration. A step provided at the close vicinity of the primary jet allows the primary jet expansion and its flow structure is affected at the entrance of the combustor to favour for jet-in-cross flow configuration. The opposed jet configuration provides large recirculation at the upstream due to merging of vortices arising from swirl of axial jet and upstream movement of primary air jet. This helps in holding the flame and also for effective combustion. However, there is a lower temperature region at the downstream core of the combustor due to penetration of primary air jets. On the other hand, jet-in-crossflow configuration has shown hotter zone at the downstream core of the combustor. Hence, effective utilization of flow structure can be considered in future design.

Genetic interaction between the non-homologous end-joining factors during B and T lymphocyte development: In vivo mouse models.

Non-homologous end joining (NHEJ) is the main DNA repair mechanism for the repair of double-strand breaks (DSBs) throughout the course of the cell cycle. DSBs are generated in developing B and T lymphocytes during V(D)J recombination to increase the repertoire of B and T cell receptors. DSBs are also generated during the class switch recombination (CSR) process in mature B lymphocytes, providing distinct effector functions of antibody heavy chain constant regions. Thus, NHEJ is important for both V(D)J recombination and CSR. NHEJ comprises core Ku70 and Ku80 subunits that form the Ku heterodimer, which binds DSBs and promotes the recruitment of accessory factors (e.g., DNA-PKcs, Artemis, PAXX, MRI) and downstream core factors (XLF, Lig4 and XRCC4). In recent decades, new NHEJ proteins have been reported, increasing complexity of this molecular pathway. Numerous in vivo mouse models have been generated and characterized to identify the interplay of NHEJ factors and their role in development of adaptive immune system. This review summarizes the currently available mouse models lacking one or several NHEJ factors, with a particular focus on early B cell development. We also underline genetic interactions and redundancy in the NHEJ pathway in mice.

Identification of the human DPR core promoter element using machine learning.

The RNA polymerase II (Pol II) core promoter is the strategic site of convergence of the signals that lead to transcription initiation1-5, but the downstream core promoter in humans has been difficult to decipher1-3. Here, we analyze the human Pol II core promoter and use machine learning to generate predictive models for the downstream core promoter region (DPR) and the TATA box. We developed a method termed HARPE (high-throughput analysis of randomized promoter elements) to create hundreds of thousands of DPR (or TATA box) variants that are each of known transcriptional strength. We then analyzed the HARPE data by support vector regression (SVR) to provide comprehensive models for the sequence motifs, and found that the SVR-based approach is more effective than a consensus-based method for predicting transcriptional activity. These studies revealed that the DPR is a functionally important core promoter element that is widely used in human promoters. Importantly, there appears to be a duality between the DPR and TATA box, as many promoters contain one or the other element. More broadly, these findings show that functional DNA motifs can be identified by machine learning analysis of a comprehensive set of sequence variants.