Indirect Regulation Research Articles

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.

Identification and analysis of differentially expressed lncRNAs and their ceRNA networks in DMD/mdx primary myoblasts

This study explored the significance of long non-coding RNAs (lncRNAs), particularly their role in maintaining dystrophin protein stability and regulating myocyte proliferation and differentiation. The investigation focused on DMD/mdx mouse skeletal muscle primary myoblasts, aiming to identify lncRNAs potential as biomarkers and therapeutic targets for Duchenne muscular dystrophy (DMD). Utilizing CLC Genomics Workbench software, 554 differentially expressed lncRNAs were identified in DMD/mdx mice compared to wild-type (WT) control. Among them, 373 were upregulated, and 181 were downregulated. The study highlighted specific lncRNAs (e.g., 5930430L01Rik, Gm10143, LncRNA1490, LncRNA580) and their potential regulatory roles in DMD key genes like IGF1, FN1, TNNI1, and MYOD1. By predicting miRNA and their connections with lncRNA and mRNA (ceRNA network) using tools such as miRNet, miRSYSTEM and miRCARTA, the study revealed potential indirect regulation of Dystrophin, IGF1R and UTRN genes by identified lncRNAs (e.g. 2310001H17Rik-203, C130073E24Rik-202, LncRNA2767, 5930430L01Rik and LncRNA580). These findings suggest that the identified lncRNAs may play crucial roles in the development and progression of DMD through their regulatory influence on key gene expression, providing valuable insights for potential therapeutic interventions.

Size-Dependent Elemental Composition in Individual Magnetite Nanoparticles Generated from Coal-Fired Power Plant Regulating Their Pulmonary Cytotoxicity.

High-resolution characterization of magnetite nanoparticles (MNPs) derived from coal combustion activities is crucial to better understand their health-related risks. In this study, size distribution and elemental composition of individual MNPs from various coal fly ashes (CFAs) collected from a representative coal-fired power plant were analyzed using a single-particle inductively coupled plasma time-of-flight mass spectrometry technique. Majority (61-80%) of MNPs were identified as multimetal (mm)-MNPs, while the contribution of single metal (sm)-MNPs to the total increased throughout all the CFAs, reaching the highest in fly ash escaped through the stack (EFA). Among Fe-rich MNPs, Fe-sole and Fe-Al matrices were predominant, and Fe-sole MNPs were identified as the important carrier for toxic metals, with the highest mass contributions of toxic metals therein. Toxic potency results showed that the oxidative stress induced by MNPs was 1.2-2.2 times greater than those of <1 μm fractions in CFAs, while the reduction in cell viability showed no significant difference, elucidating that these MNPs can induce more distinct oxidative stress compared to cell toxicity. Based on structural equation model, MNP size can both directly and indirectly regulate the toxic potency, and the indirect regulation is through a size-dependent elemental composition of MNPs, including toxic metals. sm-MNPs and Fe-rich MNPs with Fe-sole, Fe-Cr, and Fe-Zn matrices can regulate the oxidative stress, whereas Cr, Zn, and Pb associated with Fe-sole, Fe-Al, Si-Fe, and Al-Fe MNPs showed significant effects on cell viability.

Multifaceted role of microRNA-301a in human cancer: from biomarker potential to therapeutic targeting.

With the growing data on microRNA (miRNA) expression in tissues and circulation, there is increasing evidence for the potential of microRNAs to serve as biomarkers in cancer diagnosis and prognosis, as well as novel therapeutic targets. The expression level of miRNA-301a (miR-301a) is altered in a wide range of human tumor types, and numerous studies have revealed the roles of miR-301a in tumorigenesis and tumor progression. Herein, we comprehensively summarize, compare, and contrast the research advancements on the role of miR-301a in different cancers. Differential expression patterns of miR-301a in tissues and biofluids are implicated in cancer diagnosis, treatment response, and prognosis. MiR-301a modulates the expression of multiple genes, other noncoding RNAs, and signaling cascade via direct or indirect regulation in human cancer proliferation, migration, invasion, angiogenesis, and radio- or chemotherapy resistance. Cancer cell-associated miR-301a affects the tumor microenvironment through the alteration of immune function and cancer metabolism. These findings highlight the functional roles, clinical implications, and therapeutic relevance of miR-301a in various human cancers.

Functional analysis of cutinase transcription factors in Fusarium verticillioides

Fusarium verticillioides is an important pathogen of maize and causes serious yield losses and food safety issues worldwide. F. verticillioides produces highly toxic mycotoxin Fumonisin B1 (FB1) in infested commodities which makes these food and feeds unsafe for humans and animals. For pathogenic fungi to successfully penetrate its plant hosts, the pathogen secretes hydrolytic enzymes that can facilitate penetration into the plant cutin layer. However, there is limited information on how cutinases transcriptionally regulated to impact F. verticillioides pathogenicity. In this study, our aim is to functionally characterize cutinase transcription factors that regulate key cutinase activities that are directly associated with F. verticillioides pathogenicity and FB1 biosynthesis. Gene deletion of cutinase transcription factor FvCTF1α did not affect the growth and morphology of the fungal mycelia on CMII medium, whereas the conidiation, utilization of sodium acetate and sodium oleate, stress tolerance against cell wall interfering agent, and the cutinase and pectinase activities in the ΔFvctf1α mutant were negatively impacted. FvCtf1α regulates the expression of induced cutinase genes FvCUT1 and FvCUT4 by binding to their GC-rich promoters. In addition, FvCtf1α, containing a novel function in regulating FB1, interacts with the promoter of FvFUM1 and FvFUM6 to down-regulate the expression of FvFUM1 and FvFUM6, resulting in decreased production of FB1 in the ΔFvctf1α strain. ΔFvctf1α exhibited decreased pathogenicity in maize due to the down-regulation of pathogenicity-related genes as well as key downstream cutinase genes FvCUT3 and FvCUT4 in F. verticillioides. We also demonstrated that FvCtf1α regulated FvCUT3 and FvCUT4 differently; FvCUT4 via direct regulation while FvCUT3 via indirect regulation by interacting with FvFarB, a homologous protein of FvCtf1α. Moreover, RNA-seq analysis showed that FvCtf1α was associated with many pathways, such as fatty acid metabolism, carbon source utilization, cell wall integrity, oxidative stress, and fumonisin synthesis in F. verticillioides. Our study demonstrated that FvCtf1α was not only involved in the regulation of cutinases but also a broad spectrum of pathways that ultimately affect F. verticillioides virulence and mycotoxin biosynthesis.

The SINA1-BSD1 Module Regulates Vegetative Growth Involving Gibberellin Biosynthesis in Tomato.

In plants, vegetative growth is controlled by synergistic and/or antagonistic effects of many regulatory factors. Here, the authors demonstrate that the ubiquitin ligase seven in absentia1 (SINA1) mammalian BTF2-like transcription factors, Drosophila synapse-associated proteins, and yeast DOS2-like proteins (BSD1) function as a regulatory module to control vegetative growth in tomato via regulation of the production of plant growth hormone gibberellin (GA). SINA1 negatively regulates the protein level of BSD1 through ubiquitin-proteasome-mediated degradation, and the transgenic tomato over-expressing SINA1 (SINA1-OX) resembles the dwarfism phenotype of the BSD1-knockout (BSD1-KO) tomato plant. BSD1 directly activates expression of the BSD1-regulated gene 1 (BRG1) via binding to a novel core BBS (standing for BSD1 binding site) binding motif in the BRG1 promoter. Knockout of BRG1 (BRG1-KO) in tomato also results in a dwarfism phenotype, suggesting BRG1 plays a positive role in vegetative growth as BSD1 does. Significantly, GA contents are attenuated in transgenic SINA1-OX, BSD1-KO, and BRG1-KO plants exhibiting dwarfism phenotype and exogenous application of bioactive GA3 restores their vegetative growth. Moreover, BRG1 is required for the expression of multiple GA biosynthesis genes and BSD1 activates three GA biosynthesis genes promoting GA production. Thus, this study suggests that the SINA1-BSD1 module controls vegetative growth via direct and indirect regulation of GA biosynthesis in tomato.

EVOLUTION OF FORMS OF STATE REGULATION IN THE LOGISTICS SPHERE

The article summarizes the evolution of forms of state regulation in the logistics sphere. The architecture of the system of state regulation in logistics involves a structured and complex approach to the management of logistics processes at the state level. It includes several main components that interact to ensure the efficient functioning of the logistics services market. The study of the architecture of logistics systems makes it possible to clearly define their structure and functional relationships, which significantly affects the effectiveness of material flow management. Micrologistics, metallogistics, mesologistics, macrologistics and global logistics systems have their own peculiarities of state regulation. The global logistics system is an integrated network that ensures the efficient movement of goods at the international level, supporting sustainable development and competitiveness. State regulation of logistics in Ukraine is carried out through direct and indirect forms, each of which has its own characteristics and advantages. The balance between state control and market freedom is key to effective regulation of logistics. Direct and indirect regulation can be used together to achieve optimal results, taking into account the historical context and specific needs of the country. The implementation of digital technologies and innovations is an important element of modern state regulation of logistics services. Digitization, in particular the creation of a state logistics blockchain platform (DLBP), can significantly increase the transparency, efficiency and security of logistics operations at the national level. DLBP unites various participants in the logistics process, providing up-to-date data exchange and automation of business processes, which reduces bureaucratic barriers, reduces paperwork, optimizes routes and resources, and also contributes to reducing costs and delays. Research results indicate that the development of a scientific research base in the field of logistics can provide a scientific basis for effective supply chain management models. Investment in education and personnel training for the logistics industry is another important element of successful government regulation. The formation of a professional community that possesses modern knowledge and skills in the field of logistics will contribute to increasing the overall competitiveness of the national economy.

Transcriptome data are insufficient to control false discoveries in regulatory network inference

Inference of causal transcriptional regulatory networks (TRNs) from transcriptomic data suffers notoriously from false positives. Approaches to control the false discovery rate (FDR), for example, via permutation, bootstrapping, or multivariate Gaussian distributions, suffer from several complications: difficulty in distinguishing direct from indirect regulation, nonlinear effects, and causal structure inference requiring "causal sufficiency," meaning experiments that are free of any unmeasured, confounding variables. Here, we use a recently developed statistical framework, model-X knockoffs, to control the FDR while accounting for indirect effects, nonlinear dose-response, and user-provided covariates. We adjust the procedure to estimate the FDR correctly even when measured against incomplete gold standards. However, benchmarking against chromatin immunoprecipitation (ChIP) and other gold standards reveals higher observed than reported FDR. This indicates that unmeasured confounding is a major driver of FDR in TRN inference. A record of this paper's transparent peer review process is included in the supplemental information.

The effect of dynamic changes in vegetation coverage on the mechanism of organic carbon loss in inter-rill erosion

The intricate effects of dynamic variations in vegetation coverage, representing different vegetation growth states and erosion conditions, on properties (content, enrichment and loss) of sediment and soil organic carbon (SOC) fraction in inter-rill erosion have not yet been fully elucidated. By setting micro-plots with different vegetation coverage ranges (0 %, 15 ∼ 35 %, 25 ∼ 55 % and 35 ∼ 70 %), the interaction mechanisms between vegetation coverage and inter-rill erosion, particle size distribution and SOC fractions properties during the vegetation growing period were studied. The average sediment yield, runoff yield and sediment concentration were highest under the bare plot, and diminished progressively with increased vegetation coverage. The effective clay content decreased with the increasing coverage, while ultimate clay was highest in the vegetation coverage range of 25 ∼ 55 %. Clay particle was transported as aggregates, with enrichment for all treatments except for the vegetation coverage range of 35 ∼ 70 %, providing transportation potential for SOC fractions loss. The content of SOC and mineral-associated organic carbon, as well as their enrichment ratio, decreased and then increased with coverage, which is the opposite of particulate organic carbon, and the loss of all fractions decreased with increasing vegetation coverage. Mineral-associated organic carbon dominated change in SOC, with proportion in SOC content and loss decreasing first and then increasing with vegetation coverage. The structural equation model showed the impact of vegetation coverage on SOC fraction loss was mainly achieved through indirect regulation of inter-rill erosion and particle size distribution. Our results provide new insights into the complex relationship between natural slope vegetation coverage and SOC loss, particularly from a fractions perspective, as well as understanding the ultimate fate of SOC in such environments.

Mechanisms of RORα-dependent effects of melatonin

The transcription factor RORα has not traditionally been attributed a fundamental role in the development of Th17 cells, but recent studies have shown that it is necessary for the formation of a pathogenic variant of Th17 cells, the so-called Th1-polarized Th17 (Th17.1). Since the transcriptional activity of RORα depends on ligand binding, the search for such ligands is highly relevant, and in this regard, melatonin is of particular interest. The question of the ability of RORα to directly bind melatonin remains open today; data on this problem are extremely contradictory. In 1995, I. Wiesenberg and colleagues identified RORα as a nuclear receptor for melatonin, demonstrating the hormone’s ability to enhance the binding of this factor to DNA and determining the dissociation constant for the interaction of RORα with melatonin using classical Scatchard analysis. In 2011, P.J. Lardone and colleagues “rediscovered” RORα as a receptor for melatonin by demonstrating the coprecipitation of melatonin with RORα. And in 2016, A.J. Slominski and colleagues published a paper that cast doubt on the possibility of melatonin binding to RORα based on molecular modeling of ligand-receptor interactions supported by functional studies. However, a careful analysis of these data indicates the ambiguity of this conclusion, allowing us to speak, rather, of medium or low binding affinity of the hormone to RORα, but not of its absence. This conclusion is also supported by the fact that RORα mediates many of the effects of melatonin, both physiological and pharmacological, including the regulation of circadian rhythms and oxidative metabolism, neuro- and cardioprotection, and control of the immune response. In general, the data available today allow us to consider the transcription factor RORα as a receptor for melatonin with medium affinity, although indirect regulation of this factor by the hormone is not excluded, and RORα-dependent mechanisms should contribute to the cellular response to melatonin, both under physiological conditions and in the case of pharmacological use of the hormone.

Identification of Potent SFRP1 Inhibitors for Colorectal Cancer using a Comprehensive Computational Approach.

The incidence of CRC has increased worldwide over the past decade. The statistics report from WHO highlights the increased severity and fatality rate of CRC among the populations. Wnt/β-catenin is recognized as the resource for cell regeneration and cancer signaling pathways driven by frizzled receptor cofactors. Aberrant regulation of Wnt/β- catenin suppression is an important challenge in treating CRC management. The SFRP1 comprises a cysteine-rich region that is homologous to the putative Wnt-binding sites of Frizzled proteins, with the potential to impede and alter the cascade of Wnt signaling. Indirect regulation, like targeting Wnt antagonist SFRP1, is an alternative strategy to suppress the cancer signals by enhancing the apoptotic activity. Hence, this study aimed to approach the SFRP1 protein as a therapeutic target to inhibit Wnt signaling in colorectal cancer. Further, it aimed to identify the lead compounds against the SFRP1 protein, which inhibit the oncogenic expression of CRC, which might be possible using computational approaches, recognizing the importance of the SFRP1 protein role in CRC. The homology-modeled SFRP1 structure was refined, and virtual screening was performed against the anti-cancer drugs and natural drug databases to find the best hit molecules. The molecular docking, MD, and MMGBSA analysis confirmed the firm binding of SFRP1 complexes to identify the potent CRC inhibitors. The amino acid residues Arg5, Arg11, Ala13, Lys 245, Lys274, Phe147, Pro99, and Ser277 are essential for ligand binding and show similar interactions for SFRP1 complexes. The ADME/T profile for top hits is acceptable in range and obtains the drug-likeness property. The 100ns run for MD simulation confirms the stability of protein complexes. Overall, the findings of this study reveal that the lead compounds screened are capable of inhibiting SFRP1 against CRC. Targeting SFRP1 paves the way for new platforms in the field of cancer and the therapeutic sector for new approachable finds.

Ferroptosis is Involved in the Pharmacological Effect of Ginsenoside.

Ginsenoside is the principal active ingredient in ginseng. Several investigations have found that ginsenosides have anti-inflammatory, antioxidant, anti-apoptotic, anti-cancer, and antiallergic activities. Ferroptosis is an iron-dependent, non-apoptotic form of cell-regulated death caused by lipid peroxidation. Iron, lipid, and amino acid metabolism orchestrate the complex ferroptosis response through direct or indirect regulation of iron accumulation or lipid peroxidation. More and more research has demonstrated that ginsenoside impacts illnesses via ferroptosis, implying that ferroptosis might be employed as a novel target of ginsenoside for disease therapy. This article examines the molecular mechanism of ferroptosis as well as the current advancement of ginsenoside in influencing disorders via ferroptosis.

Glenohumeral Dysplasia Following Brachial Plexus Birth Injuries: A Review.

Despite the high morbidity associated with glenohumeral dysplasia (GHD) in children with brachial plexus birth injuries, the progression of this condition often remains unnoticed, even after correcting for the underlying brachial plexus birth injuries. GHD, driven by a multifactorial process involving disruptions in both direct and indirect neural regulation of bony and muscular structures, can lead to intermittent or permanent shoulder mobility imbalances, significantly impacting the quality of life of those affected. Recent research efforts are increasingly directed toward identifying the root causes, managing the deformity, and determining effective treatment options for correcting GHD. A comprehensive search strategy was used by the authors to identify relevant literature relating to the progression, pathoanatomy, clinical presentation, and management of GHD following brachial plexus birth injuries across various search engines, such as PubMed, Scopus, and Embase. Considering the topic's interdisciplinary nature, articles were retrieved from both neurosurgical and orthopaedic journals to enrich the review. Given the challenges in managing patients with brachial plexus birth injuries, a multidisciplinary care team consisting of certified occupational hand therapists, neurosurgeons, plastic surgeons, and orthopedic surgeons, specializing in brachial plexus injuries should be advocated for. The aim of this collaborative effort is to correct brachial plexus birth injuries and prevent the persistence of GHD. As research continues to focus on understanding the complexities of this condition, the aim of this review article is to summarize the current literature on the course of brachial plexus birth injury and the development of GHD. By doing so, we hope to provide neurosurgeons with the necessary knowledge and essential tools needed to identify and effectively treat GHD during management of brachial plexus birth injuries.

Identification of a LysR family transcriptional regulator that activates motility and flagellar gene expression in Vibrio parahaemolyticus.

Vibrio parahaemolyticus utilizes a polar flagellum for swimming in liquids and employs multiple lateral flagella to swarm on surfaces and in viscous environments. The VPA0961 protein is a LysR family transcriptional regulator that can regulate the swimming and swarming motility of V. parahaemolyticus, but the detailed regulatory mechanisms are not yet fully understood. Herein, we designated the protein as AcsS, which stands for activator of swimming and swarming motility. Our data provided evidence that deleting the acsS gene significantly reduced both swimming and swarming motility of V. parahaemolyticus. Furthermore, AcsS was found to activate the expression of both polar (flgA, flgM, flgB, and flgK) and lateral (motY, fliM, lafA, and fliD) flagellar genes. Overexpression of AcsS in Escherichia coli induced the expression of flgA, motY, and lafA, but did not affect the expression of flgB, flgK, flgM, fliM, and fliD. Interestingly, His-tagged AcsS did not bind to the upstream DNA regions of all the tested genes, suggesting indirect regulation. In conclusion, AcsS positively regulated the swimming and swarming motility of V. parahaemolyticus by activating the transcription of polar and lateral flagellar genes. This work enriched our understanding of the gene expression regulation within the dual flagellar systems of V. parahaemolyticus.

H3K56 acetylation affects Candida albicans morphology and secreted soluble factors interacting with the host

In recent years, epigenetics has been revealed as a mechanism able to modulate the expression of virulence traits in diverse pathogens, including Candida albicans. Indeed, epigenetic regulation can sense environmental changes, leading to the rapid and reversible modulation of gene expression with consequent adaptation to novel environments. How epigenetic changes can impact expression and signalling output, including events associated with mechanisms of morphological transition and virulence, is still poorly studied. Here, using nicotinamide as a sirtuin inhibitor, we explored how the accumulation of the H3K56 acetylation, the most prominent histone acetylation in C. albicans, might affect its interaction with the host. Our experiments demonstrate that H3K56 acetylation profoundly affects the production and/or secretion of soluble factors compromising actin remodelling and cytokine production. ChIP- and RNA-seq analyses highlighted a direct impact of H3K56 acetylation on genes related to phenotypic switching, biofilm formation and cell aggregation. Direct and indirect regulation also involves genes related to cell wall protein biosynthesis, β-glucan and mannan exposure, and hydrolytic secreted enzymes, supporting the hypothesis that the fluctuations of H3K56 acetylation in C. albicans might impair the macrophage response to the yeast and thus promote the host-immune escaping.

Effects of the pleiotropic regulator DasR on lincomycin production in Streptomyces lincolnensis

The lincoamide antibiotic lincomycin, derived from Streptomyces lincolnensis, is widely used for the treatment of infections caused by gram-positive bacteria. As a common global regulatory factor of GntR family, DasR usually exists as a regulatory factor that negatively regulates antibiotic synthesis in Streptomyces. However, the regulatory effect of DasR on lincomycin biosynthesis in S. lincolnensis has not been thoroughly investigated. The present study demonstrates that DasR functions as a positive regulator of lincomycin biosynthesis in S. lincolnensis, and its overexpression strain OdasR exhibits a remarkable 7.97-fold increase in lincomycin production compared to the wild-type strain. The effects of DasR overexpression could be attenuated by the addition of GlcNAc in the medium in S. lincolnensis. Combined with transcriptome sequencing and RT-qPCR results, it was found that most structural genes in GlcNAc metabolism and central carbon metabolism were up-regulated, but the lincomycin biosynthetic gene cluster (lmb) were down-regulated after dasR knock-out. However, DasR binding were detected with the DasR responsive elements (dre) of genes involved in GlcNAc metabolism pathway through electrophoretic mobility shift assay, while they were not observed in the lmb. These findings will provide novel insights for the genetic manipulation of S. lincolnensis to enhance lincomycin production.Key points• DasR is a positive regulator that promotes lincomycin synthesis and does not affect spore production• DasR promotes lincomycin production through indirect regulation• DasR correlates with nutrient perception in S. lincolnensis

КОСВЕННОЕ РЕГУЛИРОВАНИЕ ЦИФРОВОЙ ТРАНСФОРМАЦИИ СТРОИТЕЛЬНОЙ СФЕРЫ

The article examines the mechanisms of indirect regulation of the digital transformation of the construction industry in Russia. It analyzes the regulatory framework, including state strategies, orders, and regulations governing the implementation of digital technologies and the labeling of construction products. The article describes unified information systems and digital platforms that stimulate the transition of the construction sector to digital rails. It considers recommendations for drafting bills aimed at accelerating the digitalization of construction. The importance of an integrated approach combining digital innovations with environmental, organizational, and personnel transformations is emphasized.

Safety, tolerability, pharmacokinetics and clinical activity of AST-3424, an AKR1C3-activated bis-alkylating moiety prodrug, in subjects with advanced solid tumors in China: A phase I dose-escalation study.

3121 Background: Aldo-keto reductase family 1 member C3 (AKR1C3) modulates cellular differentiation and proliferation through indirect regulation of ligand access to hormone and nuclear receptor signaling. AKR1C3 is expressed at high levels in various human cancers, including hepatocellular carcinoma (HCC). AST-3424 is an AKR1C3-activated prodrug and releases a toxic bis-alkylating moiety (AST-2660) in the presence of AKR1C3, which forms intra- and inter-strand DNA crosslinks resulting in cell death. Here we report the results of a phase I dose escalation study of AST-3424 in patients with advanced solid tumors (NCT06239155). Methods: Patients with histologically and/or cytologically confirmed advanced solid tumors who failed standard treatment or no standard treatment, or not suitable for standard treatment were enrolled to receive AST-3424 intravenously (i.v.) at doses of 1, 2, 4, 6, 8 mg/m2 on Day 1 and Day 8 every 21 days. A parallel and accelerated titration for 1 and 2 mg/m2, and 3+3 dose escalation design for other cohorts were used to guide dose escalation and maximum tolerable dose (MTD) determination. Results: 21 subjects were enrolled and received at least one treatment (HCC=4, colorectal cancer=6, gastric cancer=4, pancreatic carcinoma=2, breast cancer=2, intrahepatic cholangiocarcinoma=1, prostate cancer=1, salivary gland cancer=1). 4 dose-limiting toxicities (DLTs) were observed (3 grade 4 platelet count decreased; 1 grade 2 gamma-glutamyltransferase increased, DLT reported due to dosing delayed more than 14 days). Safety Review Committee confirmed 6.0 mg/m2 as the MTD and recommended Phase 2 dose (RP2D). Grade≥3 adverse events (AEs) were observed in in 10 patients (47.6%). 8 patients (38.1%) had grade≥3 treatment-related AEs (TRAEs), being anemia (33.3%), platelet count decreased (19.0%), white blood cell count decreased (9.5%) and neutrophil count decreased (9.5%). Most of the grade≥3 AEs were observed in the 8.0 mg/m2 cohort. No patient had a fatal TRAE. 15 subjects with baseline target lesions had at least one post baseline assessment. 9 subjects (42.9%) had stable disease (SD); 1 subject (4.8%) had non-complete remission/non-disease progression (Non-CR/Non-PD); 5 subjects (23.8%) had progressive disease (PD). AST-3424 showed linear pharmacokinetic characteristics in the range of 1.0-8.0 mg/m2 with a half-life of 0.16-0.40 hours. AST-2660 showed linear pharmacokinetic characteristics in the range of 4.0-8.0 mg/m2 with a half-life of 1.59-2.08 hours. Conclusions: AST-3424 showed a tolerable safety profile and preliminary anti-tumor activity in advanced solid tumors. The phase II dose expansion phase of AST-3424 monotherapy is ongoing in subjects diagnosed as advanced HCC and with high AKR1C3 expression. Clinical trial information: NCT06239155 .

SMYD3 Controls Ciliogenesis by Regulating Distinct Centrosomal Proteins and Intraflagellar Transport Trafficking.

The primary cilium is a microtubule-based sensory organelle that plays a critical role in signaling pathways and cell cycle progression. Defects in the structure and/or function of the primary cilium result in developmental diseases collectively known as ciliopathies. However, the constituents and regulatory mechanisms of the primary cilium are not fully understood. In recent years, the activity of the epigenetic modifier SMYD3 has been shown to play a key role in the regulation of cell cycle progression. However, whether SMYD3, a histone/lysine methyltransferase, contributes to the regulation of ciliogenesis remains unknown. Here, we report that SMYD3 drives ciliogenesis via the direct and indirect regulation of cilia-associated components. We show that SMYD3 is a novel component of the distal appendage and is required for centriolar appendage assembly. The loss of SMYD3 decreased the percentage of ciliated cells and resulted in the formation of stumpy cilia. We demonstrated that SMYD3 modulated the recruitment of centrosome proteins (Cep164, Fbf1, Ninein, Ttbk2 and Cp110) and the trafficking of intraflagellar transport proteins (Ift54 and Ift140) important for cilia formation and maintenance, respectively. In addition, we showed that SMYD3 regulated the transcription of cilia genes and bound to the promoter regions of C2cd3, Cep164, Ttbk2, Dync2h1 and Cp110. This study provides insights into the role of SMYD3 in cilia biology and suggests that SMYD3-mediated cilia formation/function may be relevant for cilia-dependent signaling in ciliopathies.

Are there interactions between the urban and rural construction land use transition? Evidence from Jiangsu province in China

The interactive feedback between the transition of urban construction land (UCL) and rural construction land (RCL) lies at the forefront of land use transition (LUT) research, and can shape the intrinsic driving forces for land system sustainable transition and urban-rural integrated development. This study innovatively investigated the interactive feedback between UCL and RCL transition. First, a theoretical analytical framework was proposed. Second, a spatial simultaneous equation model (SSEM) was employed to examine the interactive feedback between UCL and RCL transitions in Jiangsu Province, China, from 2000 to 2020. The main findings were as follows: The interactive feedback between UCL and RCL transitions followed two paths. The first interactive feedback path was driven by the interaction of urban and rural factors, whereas the second was driven by the integrated management of urban and rural land. UCL and RCL transition witnessed a positive interactive feedback relation. Specifically, a 1% increase in UCL transition led to a 0.535% increase in RCL transition, and a 1% increase in RCL transition resulted in a 0.579% increase in UCL transition. The two aspects exhibited complex spatial interaction effects. The UCL transition in the subject city had positive and negative effects on the UCL and RCL transitions of neighboring cities, respectively. The RCL transition had positive effect on the RCL transition in neighboring cities. The key to regulation is to make the mutual feedback pathways unobstructed through innovative policies in terms of both direct and indirect regulation. This study contributes to advance research on LUT and provides scientific evidence for urban–rural integrated development.