m6A-centered crosstalk with epigenetic regulation (m6A-CT) is essential for understanding disease development and drug response. Based on different layers of epigenetic regulation, m6A-CT can be classified into four categories: m6A-centered crosstalk with histone modification (m6A-HistMod), m6A-centered crosstalk with DNA methylation (m6A-DNAMeth), m6A-centered crosstalk with RNA modification (m6A-RNAMod), and m6A-centered crosstalk with non-coding RNA (m6A-ncRNA). However, none of the existing databases has comprehensively provided the crucial data regarding m6A-CT. Therefore, a significant update was made to the M6AREG database. This updated version includes 713 entries for m6A-HistMod, 300 entries for m6A-DNAMeth, 483 entries for m6A-RNAMod, and 939 entries for m6A-ncRNA. These types of crosstalk can alter cellular pathways and processes, ultimately leading to the development of 271 categories of diseases and the response data of 205 drugs, which are regulated by 585 epigenetic regulators (including 138 regulatory proteins and 447 non-coding RNAs). Given that these data are critical for identifying diagnostic biomarkers and therapeutic targets, discovering drugs that target m6A modification, and developing combinatorial therapies to overcome drug resistance or immune evasion, this update will greatly enhance the impact of M6AREG and hold significant importance for m6A-relevant studies. The database is currently accessible to all users at: https://idrblab.org/m6areg/.

Development of targeted therapeutics begins with the discovery and validation of therapeutic targets, which builds the foundation for rational drug design. Extensive information on target–disease associations, target perturbation profiles, drug bioactivity landscapes, and clinical profiles is critical for identifying disease-relevant targets, elucidating their biological functions, and assessing the therapeutic potential. Therapeutic target database 2026 represents a major update that expands multiple layers of data essential for drug discovery. Key expansions include (i) 306 247 target–disease associations covering 2912 targets, (ii) 10 506 perturbation profiles triggered by genetic modification or chemical interference on 2368 targets, (iii) multidimensional activity landscapes of 17 806 drugs, encompassing cytotoxic, antimicrobial-, and molecular-level activities, and (iv) abundant clinical profiles for 2234 approved drugs. As a result, this update provides expanded and curated information on 3798 targets and 40 398 drugs. To enhance usability and scalability, the database framework has been rebuilt, which can be freely accessible without any login requirement at https://idrblab.org/ttd/.

As a major burden on global healthcare systems, adverse drug events (ADEs) result in significant morbidity, mortality, and healthcare resource consumption. With the rapid advances in precision medicine, personalized ADEs and their molecular mechanisms are important components of drug repurposing and drug safety improvement. Thus, extensive studies have been conducted to collect valuable information on personalized ADEs, but no database has yet been available to provide such data. In this work, PersADE, a database aiming to provide personalized drug adverse events and their molecular mechanisms, was constructed. It integrated 4 061 772 personalized drug-ADE associations, 31 756 protein-ADE associations, and 108 677 drug-protein interactions, with a particular emphasis on off-target effects. The uniqueness of these data lies in (a) providing demographic characteristics, disease context and drug administration parameters associated with ADEs, enabling stratification of drug-ADE associations; (b) systematically integrating interactions among drugs, human proteins and ADEs, describing the mechanistic insights. Given the growing global focus on precision medicine, PersADE is highly anticipated to significantly impact studies on personalized ADEs and mechanistic explorations by providing researchers and clinicians with evidence-based tools. It is now freely accessible at: https://idrblab.org/PersADE

ABSTRACT Understanding cellular responses to genetic perturbations is fundamental for drug discovery, yet experimental approaches face significant limitations in coverage and cost that prevent comprehensive mapping of cellular behavior. This has motivated the development of virtual cells—computational models that learn the relationship between cell state and function to predict the consequences of perturbations across diverse contexts. However, current computational methods suffer from limited accuracy in complex genetic interactions, poor biological interpretability, and inadequate generalization to unseen genes, severely constraining virtual cell capabilities. We present scPert, a multi-modal framework based on Transformer architecture that integrates large language model embeddings with structured biological knowledge to predict single-cell transcriptomic responses to genetic perturbations. Through hierarchical fusion of knowledge graph representations, contextual embeddings from foundation models, and gene-specific encodings, scPert achieves significant performance improvements in both single-gene and combinatorial perturbations over existing methods. In cancer-relevant applications, scPert demonstrates the capability to reveal p53 pathway dynamics and immune checkpoint regulatory mechanisms. Systematic evaluation on 42 cancer dependency genes demonstrates scPert’s ability to identify critical potential therapeutic targets. Our framework establishes a powerful computational foundation for virtual cell construction and accelerates drug target discovery.

Umbilical artery thrombosis (UAT), a rare yet critical obstetric condition, is associated with a spectrum of adverse perinatal outcomes. This retrospective study aimed to investigate the perinatal outcomes of pregnant women diagnosed with UAT at different gestational ages, and compare the neonatal outcomes between expectant management and emergency cesarean delivery following UAT diagnosis. In this retrospective study, 67 pregnant women with UAT were included and stratified into the groups of < 28 weeks (n = 8), 28–33⁺⁶ weeks (n = 30), and ≥ 34 weeks (n = 29) based on the gestational age at diagnosis. Baseline characteristics, management strategies, and perinatal outcomes were compared among the three groups. The utilization rate of low molecular weight heparin (LMWH) in the group of < 28 weeks was significantly higher than that of ≥ 34 weeks (87.50

Decidualization is a critical physiological process necessary for successful embryo implantation and pregnancy maintenance. Disruptions in this process can result in infertility and various pregnancy complications. Teneleven translocation protein 3 (TET3) is a key molecule in the dedifferentiation process, but its pathogenic mechanism remains unclear. In this study, we aimed to uncover the molecular mechanisms by which TET3 modulates decidualization through utilizing an in vitro ESC model overexpressing TET3. TET3 overexpression was found to inhibit the transcription of ITGA10 (integrin subunit alpha 10), a novel downstream target, thereby suppressing the proliferation and migration of endometrial stromal cells. This repression of ITGA10 is independent of TET3's catalytic activity and instead relies on its non-catalytic function. Mechanistically, TET3 recruits histone deacetylases 1 and 2 (HDAC1/2) to the ITGA10 promoter to repress its transcription. Silencing HDAC1 or HDAC2 individually had little effect on the repressive action of TET3. However, simultaneous knockdown of HDAC1 and HDAC2 via siRNA, or pharmacological inhibition using the HDAC1/2 inhibitor romidepsin, effectively reversed TET3-mediated repression of ITGA10. These findings uncover a non-catalytic role for TET3 in regulating decidualization and provide insights into potential therapeutic targets for pregnancy-related disorders.

ObjectivesThe therapeutic efficacy of Traditional Chinese Medicine (TCM) in modulating gut microbiota for diabetes treatment has garnered increasing scholarly attention. This study aims to meticulously examine current research trajectories and focal areas from 2004 to 2024, providing a foundational framework for future inquiries.MethodsA comprehensive search of documents published between 2004 and 2024 was conducted using the Web of Science database. The resulting data were analyzed and visualized using R software, VOSviewer, and CiteSpace.ResultsThe study included a total of 751 documents. From 2004 to 2022, the number of annual publications showed a continuous upward trend (2004: n = 1 to 2022: n = 159), and the number of publications in 2023 (n = 141) decreased slightly from the previous year. China emerged as the leading country in terms of article publications (n = 430). Additionally, the United States played a prominent role in international research collaborations. Frontiers in Pharmacology (n = 31) was the most frequently published journal, while Nature (n = 1,147) achieved the highest citation count. Key identified keywords included obesity, insulin resistance, inflammation, and oxidative stress.ConclusionThree key research focuses in this domain include: the therapeutic effects of active constituents in TCM on diabetes via gut microbiota modulation, the underlying mechanisms through which TCM influences gut microbiota in diabetes management, and the targeted regulation of specific gut bacterial populations by TCM in the treatment of diabetes.

Drug development encompasses multiple processes, wherein protein subcellular localization is essential. It promotes target identification, treatment development, and the design of drug delivery systems. In this research, a deep learning framework called LocPro is presented for predicting protein subcellular localization. Specifically, LocPro is unique in (a) combining protein representations from the pre-trained large language model (LLM) ESM2 and the expert-driven tool PROFEAT, (b) implementing a hybrid deep neural network architecture that integrates convolutional neural network (CNN), fully connected (FC) layer, and bidirectional long short-term memory (BiLSTM) blocks, and (c) developing a multi-label framework for predicting protein subcellular localization at multiple granularity levels. Additionally, a dataset was curated and divided using a homology-based strategy for training and validation. Comparative analyses show that LocPro outperforms existing methods in sequence-based multi-label protein subcellular localization prediction. The practical utility of this framework is further demonstrated through case studies on drug target subcellular localization. All in all, LocPro serves as a valuable complement to existing protein localization prediction tools. The web server is freely accessible at https://idrblab.org/LocPro/.

Purpose:Umbilical artery thrombosis (UAT) is a rare but potentially life-threatening complication in pregnancy. It shares ultrasonographic similarities with isolated single umbilical artery (iSUA), a relatively common condition with more favorable outcomes, highlighting the need for reliable differential markers. This study was performed to identify the risk factors for UAT in pregnant women. Also, we compared maternal and neonatal outcomes between UAT, iSUA, and normal controls with three umbilical vessels (NC). Patients and Methods:This retrospective study was conducted at the Women's Hospital, Zhejiang University School of Medicine. A total of 195 participants were included between January 1, 2020, and December 31, 2024, including 65 of UAT, 65 of iSUA, and 65 of NC. The baseline information, laboratory data and relevant perinatal outcomes of all participants were collected and analyzed. Logistic regression models were employed to evaluate the association between antepartum findings and UAT in pregnant women. Results:Compared with the iSUA group, the UAT group showed higher rates of abnormal fetal movement (p=0.006) and fetal heart rate (FHR) patterns (p<0.001), shorter prothrombin time (PT) (p=0.002) and lower high-density lipoprotein (HDL) levels (p=0.014). Doppler assessment demonstrated lower umbilical vascular indices in the preterm UAT participants (<37 weeks), including lower systolic/diastolic (S/D) ratios (p=0.037), pulsatility indices (PI) (p=0.005), and resistance indices (RI) (p=0.018), with two cases showing absent end-diastolic flow. Postpartum pathology revealed shorter cord length, smaller diameter, and higher hypercoiling prevalence in UAT. Multivariate analysis identified abnormal fetal movement, abnormal FHR patterns, prolonged activated partial thromboplastin time (APTT), and cord hypercoiling as the risk factors for UAT, while longer PT, higher HDL, higher umbilical vascular indices and favorable umbilical cord parameters served as the protective factors (all p<0.05). Critically, the UAT group was more likely to experience adverse maternal and neonatal outcomes than other two groups. Conclusion:This study identifies distinct clinical, laboratory data, and sonographic markers that effectively differentiate UAT from iSUA, with abnormal fetal movement and FHR patterns, prolonged APTT, and umbilical cord hypercoiling as prominent risk factors for UAT.

Target discovery is one of the essential steps in modern drug development, and the identification of promising targets is fundamental for developing first-in-class drug. A variety of methods have emerged for target assessment based on druggability analysis, which refers to the likelihood of a target being effectively modulated by drug-like agents. In the therapeutic target database (TTD), nine categories of established druggability characteristics were thus collected for 426 successful, 1014 clinical trial, 212 preclinical/patented, and 1479 literature-reported targets via systematic review. These characteristic categories were classified into three distinct perspectives: molecular interaction/regulation, human system profile and cell-based expression variation. With the rapid progression of technology and concerted effort in drug discovery, TTD and other databases were highly expected to facilitate the explorations of druggability characteristics for the discovery and validation of innovative drug target. TTD is now freely accessible at: https://idrblab.org/ttd/.

Trophoblast immune cell interactions are central events in the immune microenvironment at the maternal-fetal interface. Their abnormalities are potential causes of various pregnancy complications, including pre-eclampsia and recurrent spontaneous abortion. Matrix metalloproteinase (MMP) is highly homologous, zinc(II)-containing metalloproteinase involved in altered uterine hemodynamics, closely associated with uterine vascular remodeling. However, the interactions between MMP and the immune microenvironment remain unclear. Here we discuss the key roles and potential interplay of MMP with the immune microenvironment in the embryo implantation process and pregnancy-related diseases, which may contribute to understanding the establishment and maintenance of normal pregnancy and providing new therapeutic strategies. Recent studies have shown that several tissue inhibitors of metalloproteinases (TIMPs) effectively prevent invasive vascular disease by modulating the activity of MMP. We summarize the main findings of these studies and suggest the possibility of TIMPs as emerging biomarkers and potential therapeutic targets for a range of complications induced by abnormalities in the immune microenvironment at the maternal-fetal interface. MMP and TIMPs are promising targets for developing new immunotherapies to treat pregnancy-related diseases caused by immune imbalance.

Skin infection is a major health issue that usually is caused by the continuous proliferation of bacteria in wounds. With the abuse of antibiotics worldwide, the battle against skin infection is becoming more and more difficult. Therefore, the development of new ways with different antibacterial mechanisms to current antibiotics is urgently needed. Inspired by the powerful inhibition of ferroptosis used in cancer therapy, here in our study, ferric-loaded lipid nanoparticles (Fe-LNPs) with unform size (∼130 nm) and surface charge (∼12 mV) were constructed and found to effectively inhibit the growth of both Gram positive (Staphylococcus aureus, S. aureus) and negative (Escherichia coli, E. coli) strains, possibly due to induction of ferroptosis-like cell death mechanisms. Most importantly, Fe-LNPs can also effectively inhibit the proliferation of S. aureus in a skin infection model and promote the healing of wounds. The Fe-LNPs can be applied as a powerful antibacterial formulation for future application in clinic.

A dysregulated immune microenvironment at the maternal-fetal interface in early pregnancy may lead to early pregnancy loss, fetal growth restriction, and preeclampsia. However, major questions about how epigenetic modifications regulate the immune microenvironment during the decidualization process and embryo implantation remain unanswered. DNA methylation, the main epigenetic mechanism involved in the endometrial cycle, is crucial for specific transcriptional networks associated with endometrial stromal cell (ESC) proliferation, hormone response, decidualization, and embryo implantation. Ten-eleven translocation (TET) enzymes, responsible for catalyzing the conversion of 5-methylcytosine to 5-hydroxymethylcyosine, 5-formylytosine, and 5-carboxylcyosine to achieve the DNA demethylation process, appear to play a critical role in decidualization and embryo implantation. Here, we provide a comprehensive view of their structural similarities and the common mechanism of regulation in the microenvironment at the maternal-fetal interface during decidualization and early pregnancy. We also discuss their physiological role in the decidual immune microenvironment. Finally, we propose a key hypothesis regarding TET enzymes at the maternal-fetal interface between decidual immune cells and ESCs. Future work is needed to elucidate their functional role and examine therapeutic strategies targeting these enzymes in pregnancy-related disease preclinical models, which would be of great value for future implications in disease diagnosis or treatment.

Colorectal cancer (CRC) ranks third in incidence rate and second in mortality rate of malignancy worldwide, and the diagnosis and therapeutics of it remain to be further studied. With the emergence of noncoding RNAs (ncRNAs) and potential peptides derived from ncRNAs across various biological processes, we here aimed to identify a ncRNA-derived peptide possible for revealing the oncogenesis of CRC. Through combined predictive analysis of the coding potential of a batch of long noncoding RNAs (lncRNAs), the existence of an 85 amino-acid-peptide, named MEK1-binding oncopeptide (MBOP) and encoded from LINC01234 was confirmed. Mass spectrometry and Western blot assays indicated the overexpression of MBOP in CRC tissues and cell lines compared to adjacent noncancerous tissues and the normal colonic epithelial cell line. In vivo and in vitro migration and proliferation assays defined MBOP as an oncogenic peptide. Immunoprecipitation trials showed that MEK1 was the key interacting protein of MBOP, and MBOP promoted the MEK1/pERK/MMP2/MMP9 axis in CRC. Two E3-ligase enzymes MAEA and RMND5A mediated the ubiquitin–protease-system-related degradation of MBOP. This study indicates that MBOP might be a candidate prognostic indicator and a potential target for clinical therapy of CRC.

Abstract Context Spontaneous abortion (SA) is a common disorder in early pregnancy. Circular RNAs (circRNAs) have been reported to exert important regulatory effects on trophoblast function and embryo development. Objective The aim of this study was to explore whether and how circRNAs regulate trophoblast function in SA during early pregnancy. Methods Cell proliferation, 5-bromo-2-deoxyuridine (BrdU) staining, Transwell, immunofluorescence, Western blot, RNA pull-down, and dual luciferase reporter assays were performed to investigate the effect of circRNA cyclin B1 (circ-CCNB1) on trophoblast function in HTR-8/SVneo and JEG-3 cells. Results An in vitro study demonstrated that upregulation of circ-CCNB1 significantly inhibited trophoblast proliferation and invasion compared with the controls using HTR-8/SVneo and JEG-3 cells, respectively. Moreover, miR-223 was downregulated in the villous tissues of patients with SA and was further predicted and shown to negatively interact with circ-CCNB1, which is involved in trophoblast proliferation and invasion. Using bioinformatics tools and subsequent RNA pull-down and dual luciferase assays, we found that miR-223 directly targets seven in absentia homolog-1 (SIAH1) and that upregulation of miR-223 decreased circ-CCNB1-induced SIAH1 expression levels in HTR-8/SVneo cells. Interestingly, upregulation of circ-CCNB1 suppressed trophoblast proliferation and invasion through inhibition of CCNB1 nuclear translocation induced by SIAH1. Downregulation of SIAH1 enhanced circ-CCNB1-suppressed CCNB1 nuclear protein expression in trophoblast cells. Conclusion Circ-CCNB1 served as a modulator of trophoblast proliferation and invasion by sponging miR-223, thus forming a regulatory network of circ-CCNB1/miR-223/SIAH1 in modulating CCNB1 nuclear translocation, which enabled us to elucidate the molecular mechanisms involved in normal embryo implantation or in SA.

MicroRNA-29a (miR-29a) plays an important role in the differentiation and proliferation of various uterine cells. However, whether miR-29a can regulate the proliferation and decidualisation of endometrial stromal cells (ESCs) remain to be elucidated. Inhibition of miR-29a led to decreased decidualisation and viability of ESCs in vitro. The expression of biomarkers PRL and IGFBP1, induced by decidualisation, reduced in the absence of miR-29a, while Tetmethylcytosine dioxygenase 3 (TET3) and its potential demethylation target, the collagen type I alpha 1 chain (COL1A1), were restored. The ChIP assay demonstrated that the binding capacity of TET3 to the Col1A1 promoter could be enhanced by the inhibition of miR-29a. Our study revealed that inhibition of miR-29a suppressed the decidualisation of ESCs by enhancing the recruitment of TET3 to the promoter region of Col1A1, thus revealing the critical role of the miR-29a/TET3/Col1A1 axis involved in the regulation of endometrial decidualisation and embryo implantation during early pregnancy.

Dwarfism has been depicted in various Chinese art forms including literature, sculpture, and painting. This article examines several representative Chinese works of art from different ages of Chinese history, in order to glimpse the living situations of people with dwarfism, their professions and social status, as well as the social attitude toward them in China. We highlight "" (Shan Hai Jing, translated as the Classic of Mountains and Seas), a remarkable collection of myths and illustrations which documented the existence of dwarf communities where the residents were capable of producing high-quality grains. Representations from sculptures and paintings frequently captured the images of individuals with dwarfism in royal courts, which showed their remarkable performance skills and social ability. There are also works of art associating dwarfism with rituals. In addition to portraying ordinary individuals with humble social status, there was one particular individual with dwarfism named Yan Zi () who was highly regarded as a figure of wisdom. Throughout the long Chinese history, dwarfism had been portrayed in art as either positive, neutral or derogatory, which reflected the fact that people with dwarfism, while short in stature, are usually intellectually normal, generally skillful, and often talented, in short, like the general population.

A conceptual framework for understanding abnormal endometrial decidualization, with considerable significance for the diagnosis and treatment of abnormal decidualization-related changes in non-receptive endometrium in implantation failure during early pregnancy is very important. Here, we found the expression levels of miR-29a in endometrial tissues were associated with the menstrual phases and pregnancy outcome. Inhibition of miR-29a led to decreased decidualization of endometrial stromal cells (ESCs) in vitro, whereas Tet methylcytosine dioxygenase 3 (TET3) and its potential demethylation target, the collagen type I alpha 1 chain (Col1A1), were restored. The binding capacity of TET3 to the Col1A1 promoter could be enhanced by the inhibition of miR-29a. Finally, deletion of TET3 rescued the inhibitory effect of the miR-29a antagomir on the proliferation of decidualized ESCs in vitro and embryo implantation in vivo. Thus, loss of miR-29a causes implantation failure because of the limitation of ESCs decidualization-related changes in non-receptive endometrium during early pregnancy.