Direct Regulation Research Articles

Directional Regulation of Photogenerated Carriers in Tin Halide Perovskites for Enhanced Thermoelectrics

Directional Regulation of Photogenerated Carriers in Tin Halide Perovskites for Enhanced Thermoelectrics

High-throughput identification of calcium-regulated proteins across diverse proteomes

Calcium ions play important roles in nearly every biological process, yet whole-proteome analysis of calcium effectors has been hindered by a lack of high-throughput, unbiased, and quantitative methods to identify protein-calcium engagement. To address this, we adapted protein thermostability assays in budding yeast, human cells, and mouse mitochondria. Based on calcium-dependent thermostability, we identified 2,884 putative calcium-regulated proteins across human, mouse, and yeast proteomes. These data revealed calcium engagement of signaling hubs and cellular processes, including metabolic enzymes and the spliceosome. Cross-species comparison of calcium-protein engagement and mutagenesis experiments identified residue-specific cation engagement, even within well-known EF-hand domains. Additionally, we found that the dienoyl-coenzyme A (CoA) reductase DECR1 binds calcium at physiologically relevant concentrations with substrate-specific affinity, suggesting direct calcium regulation of mitochondrial fatty acid oxidation. These discovery-based proteomic analyses of calcium effectors establish a key resource to dissect cation engagement and its mechanistic effects across multiple species and diverse biological processes.

Dual-function natural products: Farnesoid X receptor agonist/inflammation inhibitor for metabolic dysfunction-associated steatotic liver disease therapy

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally, with only one Food and Drug Administration (FDA)-approved drug for its treatment. Given MASLD’s complex pathophysiology, therapies that simultaneously target multiple pathways are highly desirable. One promising approach is dual-modulation of the farnesoid X receptor (FXR), which regulates lipid and bile acid metabolism. However, FXR agonists alone are insufficient due to their limited anti-inflammatory effects. This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD. Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger (2018) for molecular docking. Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance (SPR) binding assay, reporter gene analysis, and reverse transcription-polymerase chain reaction (RT-PCR). The anti-inflammatory properties of these compounds were evaluated in AML12 cells treated with tumor necrosis factor-alpha (TNF-α). Dual-function compounds with FXR agonism and inflammation inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α. The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid. Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists, with 15 exhibiting a strong affinity for FXR recombinant protein. Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb. Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones. Three compounds (2, 6, and 8) were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors, while one compound (12) acted as an FXR agonist to inhibit inflammation. These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and inflammation. In conclusion, compounds 2, 6, and 8 (genistein, biochanin A, and 7-methoxyisoflavone, respectively) were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation, serving as potential candidates or lead compounds for MASLD therapy.

Hydrogel granular systems for controlled release based on (co)polymers of 2-hydroxyethyl methacrylate with polyvinylpyrrolidone (a review)

The development of polymer carriers for systems of prolonged and controlled release of substances, particularly drugs, into the action environment is a relevant task in polymer chemistry and technology. This aims to solve the problem of reducing the effective dose of a medical drug administered into the body of a person or animal. The latest achievements in the field of creating such carriers in the form of spherical particles based on 2-hydroxyethyl methacrylate and polyvinylpyrrolidone (co)polymers are analyzed and summarized. The working principles and advantages of such systems are described. The research of the synthesis regularities, structure, properties and perspectives of application of granular hydrogels based on 2-hydroxyethyl methacrylate and its copolymers with polyvinylpyrrolidone was analyzed. The mixture of decanol and cyclohexanol as a solvent for the monomer phase is substantiated. Based on the analysis of kinetic studies, the optimal technological parameters for the suspension polymerization of 2-hydroxyethyl methacrylate with polyvinylpyrrolidone were selected, and the possibility of regulating the dispersion characteristics of copolymers via changes in the technological synthesis modes was confirmed. The results of studies on the sorption-desorption properties of copolymers concerning model substances and drugs are described. The possibility of directed regulation of sorption capacity and drug release rate through changes in copolymer composition was confirmed. Methods for increasing the sorption capacity of hydrogels for drugs are proposed.

Preparation of needle coke from low-temperature coal tar pitch based on modification, component separation and component blending

Needle coke is widely used in the production of ultra-high power electrodes, special carbon materials, carbon fibers, and their composites. How to prepare needle coke with excellent performance through directional adjusting of raw material components is a hot research topic. In this paper, coal tar pitch (CTP) was extracted from low-temperature coal tar (Low-coal tar). To further increase the content of quinoline-soluble, CTP was modified by formaldehyde via chemical polymerization. By adjusting the blending ratio of hexane-insoluble toluene-soluble (HI-TS) and toluene-insoluble tetrahydrofuran-soluble (TI-AS) obtained by modified coal tar pitch (HCTP) separation adopting solvent extraction, a series of green needle coke and needle coke were prepared. The physicochemical structures were analyzed using FTIR, TG, Py-GC/MS, XRD, PM, and SEM, and the electrochemical properties were evaluated and analyzed. The results show that the Lc and La of green needle coke and needle coke firstly increase and then decrease with the decrease of TI-AS content, while the ID/IG demonstrated the opposite tendency. When the content of TI-AS is 16.67%, it is favorable to improve the micro-morphology of needle coke and increase the content of the ideal graphite lattice (from 24.47% to 31.88%) and needle coke yield (44.03%). In this paper, the composition distribution of CTP was adjusted, and the effect of the blending ratio of HI-TS and TI-AS on the structure of green needle coke and needle coke was investigated, improving the added value of Low-coal tar and providing data reference for the directional regulation of needle coke.

Direct vegetation response to recent CO2 rise shows limited effect on global streamflow

Global streamflow, crucial for ecology, agriculture, and human activities, can be influenced by elevated atmospheric CO2 (eCO2) though direct regulation of vegetation physiology and structure, which can either decrease or increase streamflow. Despite a 21.8% rise in CO2 over 40 years, its impact on streamflow is not obvious and remains highly debated. Using a full differential approach at the catchment scale and an optimum finger approach globally, both constrained by observed streamflow, here, we find that vegetation responses to eCO2 in 1981–2020 has limited impact on streamflow via direct regulation. The median eCO2 contribution approaches zero across 1116 unimpacted catchments, and global streamflow changes cannot be solely attributed to eCO2. These results offer key insights into the intricate dynamics of CO2 and other factors shaping streamflow changes over the past four decades. Such understanding is vital for attributing current streamflow changes under eCO2 conditions.

Global regulator AdpA directly binds to tunicamycin gene cluster and negatively regulates tunicamycin biosynthesis in Streptomyces clavuligerus.

Since a transcriptional regulator has yet to be identified within the tunicamycin biosynthetic gene cluster in Streptomyces clavuligerus, we conducted a comprehensive investigation by focusing on the possible function of the pleiotropic regulator AdpA on tunicamycin. The genes encoding early steps of tunicamycin biosynthesis were significantly upregulated in S. clavuligerus ΔadpA. At the same time, they were downregulated in adpA overexpressed strain as shown by RNA-sequencing (RNA-seq) and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) analysis. The tunicamycin gene cluster's co-transcription pattern was understood by reverse transcriptase polymerase chain reaction (RT-PCR). Our Electrophoretic Mobility Shift Assay (EMSA) data clearly showed AdpA's binding to the upstream sequence of the tunA gene, asserting its regulatory control. In addition to its direct negative regulation of tunicamycin biosynthesis, AdpA operates at a global level by orchestrating various regulatory genes in S. clavuligerus, such as wblA, whiB, bldM, arpA, brp, and adsA involved in morphological differentiation and secondary metabolite biosynthesis as depicted in RNA-seq data. This study represents a significant milestone by unveiling the AdpA regulator's pathway-specific and global regulatory effect in S. clavuligerus.

Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2

Mutations in GBA1 encoding the lysosomal enzyme β-glucocerebrosidase (GCase) are among the most prevalent genetic susceptibility factors for Parkinson’s disease (PD), with 10–30% of carriers developing the disease. To identify genetic modifiers contributing to the incomplete penetrance, we examined the effect of 1634 human transcription factors (TFs) on GCase activity in lysates of an engineered human glioblastoma line homozygous for the pathogenic GBA1 L444P variant. Using an arrayed CRISPR activation library, we uncovered 11 TFs as regulators of GCase activity. Among these, activation of MITF and TFEC increased lysosomal GCase activity in live cells, while activation of ONECUT2 and USF2 decreased it. While MITF, TFEC, and USF2 affected GBA1 transcription, ONECUT2 might control GCase trafficking. The effects of MITF, TFEC, and USF2 on lysosomal GCase activity were reproducible in iPSC-derived neurons from PD patients. Our study provides a systematic approach to identifying modulators of GCase activity and deepens our understanding of the mechanisms regulating GCase.

A Mechanical Immune Checkpoint Inhibitor Stiffens Tumor Cells to Potentiate Antitumor Immunity.

Tumor progression is associated with tumor-cell softening. Improving the stiffness of the tumor cells can make them more vulnerable to lymphocyte-mediated attack. Tumor cell membranes typically exhibit higher cholesterol levels than normal cells, making tumor cells soft. Herein, we demonstrate a mechanical immune checkpoint inhibitor (MICI) formulated by cyclodextrin (CD) lipids and fusogenic lipids. Through fusing CD lipids into the tumor cell membrane using a fusogenic liposome formulation, the cholesterol in the plasma membrane is reduced due to the specific host-guest interactions between CD lipid and cholesterol. As a result, tumor cells are stiffened, and the activation of lymphocytes (including NK and cytotoxic effector T cells) is improved when contacting the stiffened tumor cells, characterized by robust degranulation and effector cytokine production. Notably, this treatment has negligible influence on the infiltration and proliferation of lymphocytes in tumor tissues, confirming that the enhanced antitumor efficacy should result from activating a specific number of lymphocytes caused by direct regulation of the tumor cell stiffness. The combination of MICIs and clinical immunotherapies enhances the lymphocyte-mediated antitumor effects in two tumor mouse models, including breast cancer and melanoma. Our research also reveals an unappreciated mechanical dimension to lymphocyte activation.

YBX1 promotes epithelial-mesenchymal transition in hepatocellular carcinoma via transcriptional regulation of PLRG1.

Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer worldwide. The epithelial-mesenchymal transition (EMT) is a critical process in cancer progression, contributing to increased malignancy. While Pleiotropic Regulator 1 (PLRG1) is upregulated in HCC and is associated with enhanced cell proliferation, its oncogenic role in EMT remains unclear. In this study, we demonstrate that PLRG1 promotes EMT in HCC cells. Knockdown of PLRG1 in Huh7 cells resulted in decreased expression of the EMT markers N-cadherin and Snail, and impaired cell migration and invasion. Chromatin immunoprecipitation (ChIP) and luciferase assays identified Y-box binding protein 1 (YBX1) as a direct regulator of PLRG1 transcription, binding to its promoter region. Overexpression of YBX1 in SNU-449 cells led to increased PLRG1 expression and subsequent EMT activation, as well as enhanced migration, and invasion. These effects were attenuated by PLRG1 knockdown. Our findings indicate that YBX1 drives EMT in HCC by upregulating PLRG1, offering novel insights into the molecular mechanisms underlying HCC progression.

A Mechanical Immune Checkpoint Inhibitor Stiffens Tumor Cells to Potentiate Antitumor Immunity

Tumor progression is associated with tumor‐cell softening. Improving the stiffness of the tumor cells can make them more vulnerable to lymphocyte‐mediated attack. Tumor cell membranes typically exhibit higher cholesterol levels than normal cells, making tumor cells soft. Herein, we demonstrate a mechanical immune checkpoint inhibitor (MICI) formulated by cyclodextrin (CD) lipids and fusogenic lipids. Through fusing CD lipids into the tumor cell membrane using a fusogenic liposome formulation, the cholesterol in the plasma membrane is reduced due to the specific host–guest interactions between CD lipid and cholesterol. As a result, tumor cells are stiffened, and the activation of lymphocytes (including NK and cytotoxic effector T cells) is improved when contacting the stiffened tumor cells, characterized by robust degranulation and effector cytokine production. Notably, this treatment has negligible influence on the infiltration and proliferation of lymphocytes in tumor tissues, confirming that the enhanced antitumor efficacy should result from activating a specific number of lymphocytes caused by direct regulation of the tumor cell stiffness. The combination of MICIs and clinical immunotherapies enhances the lymphocyte‐mediated antitumor effects in two tumor mouse models, including breast cancer and melanoma. Our research also reveals an unappreciated mechanical dimension to lymphocyte activation.

Genome-wide mapping of native co-localized G4s and R-loops in living cells.

The interplay between G4s and R-loops are emerging in regulating DNA repair, replication, and transcription. A comprehensive picture of native co-localized G4s and R-loops in living cells is currently lacking. Here, we describe the development of HepG4-seq and an optimized HBD-seq methods, which robustly capture native G4s and R-loops, respectively, in living cells. We successfully employed these methods to establish comprehensive maps of native co-localized G4s and R-loops in human HEK293 cells and mouse embryonic stem cells (mESCs). We discovered that co-localized G4s and R-loops are dynamically altered in a cell type-dependent manner and are largely localized at active promoters and enhancers of transcriptional active genes. We further demonstrated the helicase Dhx9 as a direct and major regulator that modulates the formation and resolution of co-localized G4s and R-loops. Depletion of Dhx9 impaired the self-renewal and differentiation capacities of mESCs by altering the transcription of co-localized G4s and R-loops -associated genes. Taken together, our work established that the endogenous co-localized G4s and R-loops are prevalently persisted in the regulatory regions of active genes and are involved in the transcriptional regulation of their linked genes, opening the door for exploring broader roles of co-localized G4s and R-loops in development and disease.

Genome-wide mapping of native co-localized G4s and R-loops in living cells

The interplay between G4s and R-loops are emerging in regulating DNA repair, replication, and transcription. A comprehensive picture of native co-localized G4s and R-loops in living cells is currently lacking. Here, we describe the development of HepG4-seq and an optimized HBD-seq methods, which robustly capture native G4s and R-loops, respectively, in living cells. We successfully employed these methods to establish comprehensive maps of native co-localized G4s and R-loops in human HEK293 cells and mouse embryonic stem cells (mESCs). We discovered that co-localized G4s and R-loops are dynamically altered in a cell type-dependent manner and are largely localized at active promoters and enhancers of transcriptional active genes. We further demonstrated the helicase Dhx9 as a direct and major regulator that modulates the formation and resolution of co-localized G4s and R-loops. Depletion of Dhx9 impaired the self-renewal and differentiation capacities of mESCs by altering the transcription of co-localized G4s and R-loops -associated genes. Taken together, our work established that the endogenous co-localized G4s and R-loops are prevalently persisted in the regulatory regions of active genes and are involved in the transcriptional regulation of their linked genes, opening the door for exploring broader roles of co-localized G4s and R-loops in development and disease.

Alleviation of colitis by honeysuckle MIR2911 via direct regulation of gut microbiota

Inflammatory bowel disease (IBD) is a group of chronic relapsing diseases associated with inflammatory disorders and microbial dysbiosis of the intestine. The use of traditional Chinese medicine (TCM) to treat colitis has the advantage of fewer side effects, but the molecular mechanism is not clear. Recently, miRNAs have been recognized as novel functional small molecules in plants that have regulatory effects on biological activities. This study mainly investigated the mechanism of action of MIR2911 from Honeysuckle, the main component of TCM preparations for colitis. The results demonstrated that MIR2911 can be absorbed through the diet and secreted within host small extracellular vesicles (sEVs), acting directly on intestinal bacteria, reducing the abundance of Escherichia-Shigella, and improving colitis symptoms. This study provides a new theoretical basis for the molecular mechanism of TCM therapy and identifies a potential new drug a new drug target for the treatment of colitis.

Satellite measurement data-based assessment of spatiotemporal characteristics of ultraviolet index (UVI) over the state of Johor, Malaysia

The study examines the spatiotemporal and statistical characteristics of the daily ultraviolet index (UVI) over the Johor state of Malaysia. The datasets utilized in this study are the Ozone Monitoring Instrument (OMI)/Aura satellite’s daily UVI observations between October 2004 and March 2023. The innovative trend analysis (ITA) method is employed to identify the statistical trend of daily UVI. Basic statistics of daily, monthly, and seasonal UVI are also carried out to better characterize UVI in the study area. The daily UVI data collected for the analysis exhibit wide variability, with more than 80% of the daily UVI data falling above UVI 8, indicating the severity of UV radiation (UVR) reaching the study area. The monthly and seasonal UVI also display highly varying characteristics, as observed in the daily data. The pixel-based analysis of ITA results indicates a significant increasing and decreasing trend of daily UVI in the region, with values varying between − 9.42 × 10−6 and 3.79 × 10−5. However, for the study area as a whole, UVI shows a significant increasing trend of 4.50 × 10−5. The influence of parameters such as cloud optical thickness (COT), solar zenith angle (SZA), and O3 column on the strength of UVR reaching the study area is also investigated. Based on the results, the study area is characterized by low thickness, broken clouds, and sometimes cloudless conditions. Overall, the results show that UVI in the study area is increasing, and therefore, proper health guidelines and direct UVR exposure regulations need to be implemented to reduce serious health risks associated with UVR exposure.Graphical

The MADS-box gene XAANTAL1 participates in Arabidopsis thaliana primary root growth and columella stem cell patterns in response to ROS, via direct regulation of PEROXIDASE 28 and RETINOBLASTOMA RELATED.

The balance between cell growth, proliferation and differentiation emerges from gene regulatory networks coupled to various signal transduction pathways, including reactive oxygen species (ROS) and transcription factors (TFs), enabling developmental responses to environmental cues. The Arabidopsis thaliana's primary root has become a valuable system for unraveling such networks. Recently, the role of TFs that mediate the ROS's inhibition of primary root growth has begun to be characterized. This study demonstrates that the MADS-box transcription factor XAANTAL1 (XAL1) is an essential regulator of hydrogen peroxide (H2O2) in primary root growth and root stem cell niche identity. Interestingly, our findings suggest that XAL1 acts as a positive regulator of H2O2 concentration in the root meristem by directly regulating genes involved in oxidative stress response, such as PEROXIDASE 28 (PER28). Moreover, we found that XAL1 is necessary for the H2O2-induced inhibition of primary root growth through the negative regulation of peroxidase and catalase activities. Furthermore, XAL1, in conjunction with RETINOBLASTOMA-RELATED (RBR), is essential for positively regulating the differentiation of columella stem cells and for participating in primary root growth inhibition in response to oxidative stress induced by H2O2 treatment.

Directional regulation on single-molecule redox-targeting reaction in neutral zinc-iron flow batteries

Directional regulation on single-molecule redox-targeting reaction in neutral zinc-iron flow batteries

Direct Evidence for Microbial Regulation of the Temperature Sensitivity of Soil Carbon Decomposition.

Soil physicochemical protection, substrates, and microorganisms are thought to modulate the temperature sensitivity of soil carbon decomposition (Q10), but their regulatory roles have yet to be distinguished because of the confounding effects of concurrent changes of them. Here, we sought to differentiate these effects through microorganism reciprocal transplant and aggregate disruption experiments using soils collected from seven sites along a 5000-km latitudinal transect encompassing a wide range of climatic conditions and from a 4-year laboratory incubation experiment. We found direct microbial regulation of Q10, with a higher Q10 being associated with greater fungal:bacterial ratios. However, no significant direct effects of physicochemical protection and substrate were observed on the variation in Q10 along the latitudinal transect or among different incubation time points. These findings highlight that we should move forward from physicochemical protection and substrate to microbial mechanisms regulating soil carbon decomposition temperature sensitivity to understand and better predict soil carbon-climate feedback.

Pre-trial protocol in civil proceedings

The scientific article examines the legal nature of the pre-trial protocol in civil proceedings. The institution of judicial evidence was subject to change in connection with the latest reforms of the civil procedure legisla-tion. This has led to the emergence of new institutions and the pre-trial protocol in civil proceedings is such. Until 2022, the Civil Procedure Code of the Republic of Kazakhstan (hereinafter CPC RK) did not have di-rect legal regulation of this institution, and accordingly, no theoretical studies were conducted on this issue. In civil proceedings, the prototype of the institute of pre-trial protocol was a foreign legal institution, such as the disclosure of evidence and the exchange of arguments, characteristic of English and American procedural law. The practical necessity of many aspects of such a phenomenon as the pre-trial protocol, the incomplete-ness of theoretical developments and the need to improve legislation determined the relevance of the topic of the scientific article. It should be recognized that the mechanism for drawing up a pre-trial protocol, in fact, designed to ensure the implementation of the principles of competition and equality of the parties, was not sufficiently enshrined in the civil procedural legislation of the Republic of Kazakhstan. At the same time, consistent legislative regulation of the activities of bodies for the disclosure of evidence in civil proceedings is required. The institution of pre-trial protocol in civil proceedings requires regulation and integration at the legislative level, since the mechanism of conclusion in the current CPC of the Republic of Kazakhstan has not been fully investigated.

Supply and demand analysis and security pattern optimization of flood regulation ecosystem services adapted to the complex terrain of coastal estuaries: A case study in Xiamen

The flood risk in coastal areas has been exacerbated by global climate change. Research on flood risk assessment is emerging from the perspective of supply and demand for flood regulation ecosystem services (FRES). However, there are still limitations in the evaluation of lowland regulation, implementation of intelligent algorithms, comparison of multi-grain FRES supply and demand, and overall optimization of security pattern. Therefore, we propose a comprehensive FRES supply assessment method that incorporates soil and vegetation, lowland, and water regulations. Additionally, we introduce the random forest model to enhance the FRES demand assessment approach. Two grain sizes of the sub-catchment area and grid unit are used to compare FRES supply and demand. Using Xiamen as a case study, this research unveils the following findings: (1) Significant disparities exist between the assessment outcomes of FRES based on multiple types of regulatory services and those solely considering soil and vegetation regulation. The areas with high FRES supply extend beyond upper mountain forests to include local lower plains exhibiting strong capabilities for lowland or water system regulation. (2) Consistent yet distinct results are observed when comparing two grain sizes. Imbalances in supply and demand occur in estuaries, bays, and densely built-up regions. Sub-catchment units exhibit wider distribution and concentration, while grid units display more dispersed patterns. (3) In terms of in-situ regulation, 26.77 km2 ecological protection area, 9.85 km2 ecological restoration area, and 119.59 km2 construction land flood control intervention area are demarcated. From a directional regulation perspective, 22 FRES corridors connecting source and sink areas along with 24 pinch points are identified. Optimizing security patterns through coordinated management of FRES supply and demand can enhance the resilience of coastal estuaries.