Key Events Research Articles

Identification of Necroptosis-related Molecular Subtypes and Construction of Necroptosis-related Gene Signature for Glioblastoma Multiforme.

Necroptosis is a highly regulated and genetically controlled process, and therefore, attention has been paid to the exact effects of this disorder on a variety of diseases, including cancer. An in-depth understanding of the key regulatory factors and molecular events that trigger necroptosis can not only identify patients at risk of cancer development but can also help to develop new treatment strategies. This study aimed to increase understanding of the complex role of necroptosis in glioblastoma multiforme (GBM) and provide a new perspective and reference for accurate prediction of clinical outcomes and gene-targeted therapy in patients with GBM. The objective of this study was to analyze the gene expression profile of necroptosis regulatory factors in glioblastoma multiforme (GBM) and establish a necroptosis regulatory factor-based GBM classification and prognostic gene signature to recognize the multifaceted impact of necroptosis on GBM. The necroptosis score of the glioblastoma multiforme (GBM) sample in TCGA was calculated by ssGSEA, and the correlation between each gene and the necroptosis score was calculated. Based on necroptosis score-related genes, unsupervised consensus clustering was employed to classify patients. The prognosis, tumor microenvironment (TME), genomic changes, biological signal pathways and gene expression differences among clusters were analyzed. The gene signature of GBM was constructed by Cox and LASSO regression analysis of differentially expressed genes (DEGs). Based on 34 necroptosis score-related genes, GBM was divided into two clusters with different overall survival (OS) and TME. A necroptosis-related gene signature (NRGS) containing 8 genes was developed, which could stratify the risk of GBM in both the training set and verification set and had good prognostic value. NRGS and age were both independent prognostic indicators of GBM, and a nomogram developed by the integration of both of them showed a better predictive effect than traditional clinical features. In this study, patients from public data sets were divided into two clusters and the unique TME and molecular characteristics of each cluster were described. Furthermore, an NRGS was constructed to effectively and independently predict the survival outcome of GBM, which provides some insights for the implementation of personalized precision medicine in clinical practice.

Identification of Key Prognostic Alternative Splicing Events of Costimulatory Molecule-Related Genes in Colon Cancer.

This study aimed to explore the key alternative splicing events in costimulatory molecule-related genes in colon cancer and to determine their correlation with prognosis. Gene expression RNA-sequencing data, clinical data, and SpliceSeq data of colon cancer were obtained from The Cancer Genome Atlas. Differentially expressed alternative splicing events in genes were identified, Followed by correlation analysis of genes corresponding to differentially expressed alternative splicing events with costimulatory molecule-related genes. Survival analysis was conducted using differentially expressed alternative splicing events in these genes and a prognostic model was constructed. Functional enrichment, proteinprotein interaction network, and splicing factor analyses were performed. In total, 6504 differentially expressed alternative splicing events in 3949 genes were identified between tumor and normal tissues. Correlation analysis revealed 3499 differentially expressed alternative splicing events in 2168 costimulatory molecule-related genes. Moreover, 328 differentially expressed alternative splicing events in 288 costimulatory molecule-related genes were associated with overall survival. The prognostic models constructed using these showed considerable power in predicting survival. The ubiquitin A-52 residue ribosomal protein fusion product 1 and ribosomal protein S9 were the hub nodes in the protein-protein interaction network. Furthermore, one splicing factor, splicing factor proline and glutamine-rich, was significantly associated with patient prognosis. Four splicing factor-alternative splicing pairs were obtained from four alternative splicing events in three genes: TBC1 domain family member 8 B, complement factor H, and mitochondrial fission 1. The identified differentially expressed alternative splicing events of costimulatory molecule-related genes may be used to predict patient prognosis and immunotherapy responses in colon cancer.

Kenaf Seed Cysteine Protease (KSCP) Inhibits the Intrinsic Pathway of the Blood Coagulation Cascade and Platelet Aggregation.

Thrombosis is the key event that obstructs the flow of blood throughout the circulatory system, leading to stroke, myocardial infarction and severe cardiovascular complications. Currently, available antithrombotic drugs trigger several life-threatening side effects. Antithrombotic agents from natural sources devoid of adverse effects are grabbing high attention. In our previous study, we reported the antioxidant, anticoagulant and antiplatelet properties of kenaf seed protein extract. Therefore, in the current study, purification and characterization of cysteine protease from kenaf seed protein extract responsible for potential antithrombotic activity was undertaken. Purification of KSCP (Kenaf Seed Cysteine Protease) was carried out using gel permeation and ion exchange column chromatography. The purity of the enzyme was evaluated by SDS PAGE (Sodium Dodecyl-Sulfate Polyacrylamide Gel Electrophoresis). RP-HPLC (Reverse Phase High-Performance Liquid Chromatography), MALDI-TOF (Matrix-Assisted Laser Desorption Ionization Time-Of-Flight) and CD (Circular Dichroism techniques) were employed for its characterization. Proteolytic, fibrinolytic and kinetic study was done using spectroscopy. Plasma recalcification time, Prothrombin Time (PT), Thrombin clotting time (TCT), Activated Partial Thromboplastin Time (APTT), bleeding time and platelet aggregation studies were carried out for antithrombotic activity of KSCP. A single sharp band of KSCP was observed under both reduced and non-reduced conditions, having a molecular mass of 24.1667kDa. KSCP was found to contain 30.3% helix turns and 69.7% random coils without a beta-pleated sheet. KSCP digested casein and fibrin, and its activity was inhibited by iodoacetic acid (IAA). KSCP was optimally active at pH 6.0 at the temperature of 40°C. KSCP exhibited anticoagulant properties by interfering in the intrinsic pathway of the blood coagulation cascade. Furthermore, KSCP dissolved both whole blood and plasma clots and platelet aggregation. KSCP purified from kenaf seed extract showed antithrombotic potential. Hence, it could be a better candidate for the management of thrombotic complications.

Understanding government social media communication strategies and public engagement during the COVID-19 crisis in Lebanon

The COVID-19 pandemic has prompted governments to adopt various online communication strategies, including the use of social media platforms. Drawing on the crisis and emergency risk communication model, this study investigates the Facebook communication strategies employed by the Ministry of Public Health (MoPH) during the COVID-19 crisis in Lebanon and examines the public engagement with these efforts. A content analysis was conducted on 2,001 posts related to COVID-19 from January 2020 to June 2021. The posts were classified into categories and the frequency and median were used to measure government posting activity and engagement. The study analyzed additional post features such as hashtags, mentions, captions, and language to provide further context to the findings. Trend analysis was also conducted to examine how the metrics varied with key events. The results show that MoPH predominantly used photos (72.00%) and the majority of its posts were published during the initial phase of the outbreak (74.20%). The most prevalent categories of posts were uncertainty reduction (54.57%), self-efficacy (30.33%), and vaccines and immunization (16.89%). MoPH’s Facebook page witnessed a surge in followers during the post-COVID-19 period, increasing by over 300.00% from the pre-COVID-19 years. Posts content, media type, and crisis stage influenced the level of public engagement. The study reveals that Facebook is effective for strategic health crisis communication. Furthermore, it provides practical insights for public sector emergency managers responsible for online communication during outbreaks.

Assessment of the mode of action of perchloroethylene-induced mouse liver tumors.

Perchloroethylene (PCE) is used as a solvent and chemical intermediate. Following chronic inhalation exposure, PCE selectively induced liver tumors in mice. Understanding the mode of action (MOA) for PCE carcinogenesis in mice is important in defining its possible human cancer risk. The proposed MOA is based on the extensive examination of the peer-reviewed studies that have assessed the mouse liver effects of PCE and its major oxidative metabolite trichloroacetic acid (TCA). Similar to PCE, TCA has also been demonstrated to liver tumors selectively in mice following chronic exposure. The Key Events (KE) of the proposed PCE MOA involve oxidative metabolism of PCE to TCA [KE 1]; activation of the peroxisome proliferator-activated receptor alpha (PPARα) [KE 2]; alteration in hepatic gene expression including cell growth pathways [KE 3]; increase in cell proliferation [KE 4]; selective clonal expansion of hepatic preneoplastic foci [KE 5]; and formation of hepatic neoplasms [KE 6]. The scientific evidence supporting the PPARα MOA for PCE is strong and satisfies the requirements for a MOA analysis. The PPARα liver tumor MOA in rodents has been demonstrated not to occur in humans; thus, human liver cancer risk to PCE is not likely.

Self-reported history of breastfeeding in relation to recalled age at menarche in the United States.

Menarche is a key life history event that shapes the female reproductive trajectory and is important to the study of human biology because of the associated epidemiological and social consequences later in life. Our question is whether breastfeeding is associated with the variation in timing of menarche. Using data from a college-aged female student population from Amherst, MA, we examined whether having been breastfed was associated with age at menarche. Of the 340 female participants with information on breastfeeding during infancy, we found that women who were breastfed (n = 286) had an adjusted mean age of menarche of 12.53 years (SE 0.09), while those who were not breastfed (n = 54) had an adjusted mean age of menarche of 12.04 years (SE 0.20; p < 0.03). We propose further research that explores a finer distinction between formula-fed, mixed-fed or predominantly breastfed infants, duration of breastfeeding and age at menarche.

Early and contemporary drivers of the HIV-1 group M pandemic.

HIV emerged silently taking time to spread and become visible only through geographically isolated clusters of life-threatening immunodeficiency, known as AIDS since the early 80s. The clusters of infection expanded, overlapping to evolve into a pandemic that is ongoing and almost as silent. Phylogenetic analysis places the emergence of HIV-1 group M, the subtype responsible for the pandemic, in the human population more than 100 years ago. Once established, the rate and direction of spread of HIV-1 from local, to national, to contemporary pandemic proportions have varied over time and place. The literature presents many theories on the emergence and drivers of the spread of the virus over the past century. Here, historical evidence and phylogenetic models are reviewed to seek clarity on the emergence, geographic spread and key world events that mark the progression of the HIV-1 pandemic. This narrative review places particular focus on: war (both its direct and indirect affects), trade and economic expansion, changes in sexual behaviors, and public health policy. Investigating the impact of major world events and policy on the emergence and spread of HIV-1 may aid better understanding of what influences the viruses transmission dynamic. By identifying multilateral targets that influence transmission, up-scaled efforts to effectively control, if not remove, HIV-1 from the human population become a possibility. Suggestions for revisions in HIV-1 global public health policy are discussed. Refocused efforts to tackle HIV-1 transmission and replace the need to manage the pathology of this terrible disease are both ethically and economically just.

Uncovering a multitude of stage-specific splice variants and putative protein isoforms generated along mouse spermatogenesis.

Mammalian testis is a highly complex and heterogeneous tissue. This complexity, which mostly derives from spermatogenic cells, is reflected at the transcriptional level, with the largest number of tissue-specific genes and long noncoding RNAs (lncRNAs) compared to other tissues, and one of the highest rates of alternative splicing. Although it is known that adequate alternative-splicing patterns and stage-specific isoforms are critical for successful spermatogenesis, so far only a very limited number of reports have addressed a detailed study of alternative splicing and isoforms along the different spermatogenic stages. In the present work, using highly purified stage-specific testicular cell populations, we detected 33,002 transcripts expressed throughout mouse spermatogenesis not annotated so far. These include both splice variants of already annotated genes, and of hitherto unannotated genes. Using conservative criteria, we uncovered 13,471 spermatogenic lncRNAs, which reflects the still incomplete annotation of lncRNAs. A distinctive feature of lncRNAs was their lower number of splice variants compared to protein-coding ones, adding to the conclusion that lncRNAs are, in general, less complex than mRNAs. Besides, we identified 2,794 unannotated transcripts with high coding potential (including some arising from yet unannotated genes), many of which encode unnoticed putative testis-specific proteins. Some of the most interesting coding splice variants were chosen, and validated through RT-PCR. Remarkably, the largest number of stage-specific unannotated transcripts are expressed during early meiotic prophase stages, whose study has been scarcely addressed in former transcriptomic analyses. We detected a high number of yet unannotated genes and alternatively spliced transcripts along mouse spermatogenesis, hence showing that the transcriptomic diversity of the testis is considerably higher than previously reported. This is especially prominent for specific, underrepresented stages such as those of early meiotic prophase, and its unveiling may constitute a step towards the understanding of their key events.

A Comparative Study and Analysis of the History and Recent Development of Real Estate in Hong Kong and the Mainland

Since the resumption of customs between Hong Kong and the Mainland, exchanges between the two places have become increasingly close. With the stabilisation of connectivity between the two places and the recovery of the Mainland economy, the transaction volume of Hong Kong's real estate market has been rising. This paper compares and analyzes the real estate development in Hong Kong and the mainland, on the one hand, analyzes the real estate development history of the two places, in particular, focuses on the impact of key historical events and policies on Hong Kong's real estate, and on the other hand, compares the development status of real estate in the two places in recent years, so as to understand the characteristics and development trends of the real estate markets in the two places, and provides reference for policy formulation and investment decision-making in the context of the close connection between the real estate in the two places after the reopening of the border. At the same time, it looks forward to the development trend of real estate in Hong Kong and mainland China, predicts possible challenges and opportunities, and puts forward reasonable policy suggestions and coping strategies. The results of the study show that the development of real estate in the Mainland is more affected by the political environment and is different from that of Hong Kong in terms of economy, policy and society; the lack of land supply has become an inevitable trend in both places, and it is necessary to solve the problem in a multi-faceted manner.

The die-hards, negotiators and migrants: Portraits of doctors' career pathways through specialisation.

Global workforce shortages in medical specialties strain healthcare systems, jeopardising patient outcomes. Enhancing recruitment strategies by supporting professional identity (PI) development may be one way to address this workforce gap-yet little research has explored this topic. The goal of the current study was to explore specialty-specific recruitment through considering PI. As proposed causes of workforce shortages in anatomical pathology (AP) bear similarities to many other specialties, this study uses the field of AP as a model for specialist PI development and asks: (1) why, how and when do doctors choose to pursue AP training and (2) what can be learned from this for recruitment to AP and other specialties? A qualitative research approach was undertaken using narrative inquiry. Interviews with junior doctors interested in AP, AP registrars and AP consultants from Australia and New Zealand were interpreted as stories via 're-storying'. Narrative synthesis of participants' collective stories identified chronological key events (i.e. 'turning points') in choosing AP. Narrative synthesis resulted in identification of three portraits entering medical specialist training: (1) die-hards, deciding upon initial exposure; (2) negotiators, choosing after comparing specialties; and (3) migrants, seeking to move away from non-pathology specialties. The negotiators and migrants cemented their decision to pursue AP as a postgraduate doctor, whereas the die-hards made this decision during medical school. Given the similarities in portrait traits between AP and other specialties across the literature, our results suggest ways to support specialty recruitment using PI development. We propose a medical specialist recruitment framework to support the PI development of doctors with die-hard, negotiator and migrant traits. Use of this framework could enhance current specialty-specific recruitment approaches, particularly in fields challenged by workforce shortages.

The epoch of the Milky Way’s bar formation: dynamical modelling of Mira variables in the nuclear stellar disc

ABSTRACT A key event in the history of the Milky Way is the formation of the bar. This event affects the subsequent structural and dynamical evolution of the entire Galaxy. When the bar formed, gas was likely rapidly funnelled to the centre of the Galaxy settling in a star-forming nuclear disc. The Milky Way bar formation can then be dated by considering the age distribution of the oldest stars in the formed nuclear stellar disc. In this highly obscured and crowded region, reliable age tracers are limited, but bright, high-amplitude Mira variables make useful age indicators as they follow a period–age relation. We fit dynamical models to the proper motions of a sample of Mira variables in the Milky Way’s nuclear stellar disc region. Weak evidence for inside-out growth and both radial and vertical dynamical heating with time of the nuclear stellar disc is presented, suggesting that the nuclear stellar disc is dynamically well-mixed. Furthermore, for Mira variables around a ∼350-d period, there is a clear transition from nuclear stellar disc-dominated kinematics to background bar-bulge-dominated kinematics. Using a Mira variable period–age relation calibrated in the solar neighbourhood, this suggests the nuclear stellar disc formed in a significant burst in star formation $(8\pm 1)\, \mathrm{Gyr}$ ago, although the data are also weakly consistent with a more gradual formation of the nuclear stellar disc at even earlier epochs. This implies a relatively early formation time for the Milky Way bar ($\gtrsim 8\, \mathrm{Gyr}$), which has implications for the growth and state of the young Milky Way and its subsequent history.

Detection of nitric oxide-mediated metabolic effects using real-time extracellular flux analysis.

Dendritic cell (DC) activation is marked by key events including: (I) rapid induction and shifting of metabolism favoring glycolysis for generation of biosynthetic metabolic intermediates and (II) large scale changes in gene expression including the upregulation of the antimicrobial enzyme inducible nitric oxide synthase (iNOS) which produces the toxic gas nitric oxide (NO). Historically, acute metabolic reprogramming and NO-mediated effects on cellular metabolism have been studied at specific timepoints during the DC activation process, namely at times before and after NO production. However, no formal method of real time detection of NO-mediated effects on DC metabolism have been fully described. Here, using Real-Time Extracellular Flux Analysis, we experimentally establish the phenomenon of an NO-dependent mitochondrial respiration threshold, which shows how titration of an activating stimulus is inextricably linked to suppression of mitochondrial respiration in an NO-dependent manner. As part of this work, we explore the efficacy of two different iNOS inhibitors in blocking the iNOS reaction kinetically in real time and explore/discuss parameters and considerations for application using Real Time Extracellular Flux Analysis technology. In addition, we show, the temporal relationship between acute metabolic reprogramming and NO-mediated sustained metabolic reprogramming kinetically in single real-time assay. These findings provide a method for detection of NO-mediated metabolic effects in DCs and offer novel insight into the timing of the DC activation process with its associated key metabolic events, revealing a better understanding of the nuances of immune cell biology.

Tracking Mississippian Migrations from the Central Mississippi Valley to the Ridge and Valley with a Unified Absolute Chronology

AbstractAs regional chronologies become better defined, we are better able to track large-scale population movements and related cultural change. A dataset of 156 radiocarbon dates from the Middle Cumberland Region (MCR), evaluated with 199 more dates from the Ridge and Valley portions of northern Georgia and East Tennessee, enable modeling of population movements from the Central Mississippi Valley into the MCR, as well as subsequent movements and effects in the Ridge and Valley between AD 1200 and 1450. The dissolution of Cahokia is of particular interest, because the MCR falls geographically between the American Bottom and the Ridge and Valley province. This large-scale chronological perspective places key events in this part of the Southeast and Midwest into a unified historical framework that increases our understanding of the timing of cultural events. A related goal is to sort out possible external events and influences that may have affected this large region. This study makes apparent the relationships between cultural events and natural events, such as the drought sequences reported for the Central Mississippi Valley and beyond.

Disruption of gonadotropin hormone biosynthesis by parabens: A potential development and reproduction-associated adverse outcome pathway

Parabens are widely used as antibacterial preservatives in foods and personal care products. The knowledge about the modes of toxic action of parabens on development and reproduction remain very limited. The present study attempted to establish a development and reproduction-associated adverse outcome pathway (AOP) by evaluating the effects of methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP) on the biosynthesis of gonadotropins, which are key hormones for development and reproduction. MP and BP significantly upregulated the mRNA and protein levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in pituitary gonadotropic cells in a concentration-dependent manner. Activation of gonadotropin-releasing hormone receptor (GnRHR) was required for gonadotropin biosynthesis induced by BP, but not MP. Molecular docking data further demonstrated the higher binding efficiency of BP to human GnRHR than that of MP, suggesting GnRHR as a potential molecular initiative event (MIE) for BP-induced gonadotropin production. L-type voltage-gated calcium channels (VGCCs) were found to be another candidate for MIE in gonadotropic cells response to both MP and BP exposure. The calcium-dependent activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2 was subsequently required for MP- and BP-induced activation of GnRHR and L-type VGCCs pathways. In summary, MP and BP promoted gonadotropin biosynthesis through their interactions with cellular macromolecules GnRHR, L-type VGCCs, and subsequent key event ERK1/2. This is the first study to report the direct interference of parabens with gonadotropin biosynthesis and establish a potential AOP based on pathway-specific mechanism, which contributes to the effective screening of environmental chemicals with developmental and reproductive health risks.

Diazoxide attenuates DOX-induced cardiotoxicity in cultured rat myocytes.

Doxorubicin (DOX)-induced cardiotoxicity is a well known clinical problem, and many investigations have been made of its possible amelioration. We have investigated whether diazoxide (DIA), an agonist at mitochondrial ATP-sensitive potassium channels (mitoKATP), could reverse DOX-induced apoptotic myocardial cell loss, in cultured rat cardiomyocytes. The role of certain proteins in this pathway was also studied. The rat cardiomyocyte cell line (H9c2) was treated with DOX, and also co-treated with DOX and DIA, for 24 h. Distribution of actin filaments, mitochondrial membrane potential, superoxide dismutase (SOD) activity, total oxidant and antioxidant status (TOS and TAS, respectively), and some protein expressions, were assessed. DOX significantly decreased SOD activity, increased ERK1/2 protein levels, and depolarised the mitochondrial membrane, while DIA co-treatment inhibited such changes. DIA co-treatment ameliorated DOX-induced cytoskeletal changes via F-actin distribution and mitoKATP structure. Co-treatment also decreased ERK1/2 and cytochrome c protein levels. Cardiomyocyte loss due to oxidative stress-mediated apoptosis is a key event in DOX-induced cytotoxicity. DIA had protective effects on DOX-induced cardiotoxicity, via mitoKATP integrity, especially with elevated SUR2A levels; but also by a cascade including SOD/AMPK/ERK1/2. Therefore, DIA may be considered a candidate agent for protecting cardiomyocytes against DOX chemotherapy.

Abstract A102: ROR2/Wnt5a signaling regulates directional cell migration and early tumor cell invasion in ovarian cancer

Abstract Adhesion to and clearance of the mesothelial monolayer are key events in the early metastatic seeding of ovarian cancer. To identify mediators of ovarian cancer cell adhesion and invasion, we developed and conducted a cellular, high-throughput genetic screen using a human kinome siRNA library. Through this screen, we identified ROR2 as a driver of ovarian cancer adhesion and invasion. ROR2 is a receptor tyrosine kinase that interacts with Wnt5a ligand to activate non-canonical Wnt signaling and has been previously shown to be upregulated in ovarian cancer tissue. However, no prior study has evaluated the mechanistic role of ROR2 in ovarian cancer. Using in vitro adhesion and mesothelial clearance assays, we show that ROR2 promotes ovarian cancer cell adhesion and clearance of the mesothelial monolayer, key early steps in ovarian cancer metastasis. Further, we show that depletion of ROR2 reduces metastatic tumor burden in a syngeneic mouse model of ovarian cancer. Additionally, using a microfluidic device capable of producing stable fluid gradients, we demonstrate that ROR2 expression in ovarian cancer cells serves to drive directed cell migration of tumor cells, preferentially to areas of high Wnt5a ligand. As Wnt5a has been previously shown to be produced and upregulated in the mesothelial cells of the ovarian cancer microenvironment, these findings represent a novel role for ROR2 to promote the homing of ovarian tumor cells to the mesothelial lined metastatic niche by using Wnt5a as a chemotactic cue. These findings support the role of ROR2 as a critical factor contributing to the steps of ovarian cancer metastasis. Therapeutic targeting of the ROR2/Wnt5a signaling axis could provide a means of improving treatment for patients with advanced ovarian cancer. Citation Format: Whitney R. Grither, Breanna Baker, Vasilios A. Morikis, Katherine C. Fuh, Gregoery D Longmore. ROR2/Wnt5a signaling regulates directional cell migration and early tumor cell invasion in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A102.

C5b-9 promotes ferritinophagy leading to ferroptosis in renal tubular epithelial cells of trichloroethylene-sensitized mice

Trichloroethylene (TCE) is a common environmental contaminant that can cause a severe allergic reaction called TCE hypersensitivity syndrome, which often implicates the patient's kidneys. Our previous study revealed that C5b-9-induced tubular ferroptosis is involved in TCE-caused kidney damage. However, the study did not explain how tubule-specific C5b-9 causes free iron overload, a key event in ferroptosis. Here, we aimed to explore the role of NCOA4-mediated ferritinophagy in C5b-9-induced iron overload and ferroptosis in TCE-sensitized mice. Our results showed that TCE sensitization does not affect iron import or export, but does affect iron storage, causing ferritin degradation and free iron overload. In addition, mitochondrial ROS was upregulated, and these changes were blocked by C5b-9 inhibition. Interestingly, TCE-induced ferritin degradation and ferroptosis were significantly antagonized by the application of the mitochondrial ROS inhibitor, Mito-TEMPO. Moreover, all of these modes of action were further verified in C5b-9-attack signalling HK-2 cells. Further investigation demonstrated that C5b-9-upregulated mitochondrial ROS induced a marked increase in nuclear receptor coactivator 4 (NCOA4), a master regulator of ferritinophagy. In addition, the application of NCOA4 small interfering RNA not only significantly reversed ferritinophagy caused by C5b-9 but also reduced C5b-9-induced ferroptosis in HK-2 cells. Taken together, these results suggest that tubule-specific C5b-9 deposition activates NCOA4 through the upregulation of mitochondrial ROS, causing ferritin degradation and elevated free iron, which ultimately leads to tubular epithelial cell ferroptosis and kidney injury in TCE-sensitized mice.

Abstract B093: Investigating early events of ovarian cancer transcoelomic metastasis identifies the small Rho-GTPase RHOV as an essential gene for cellular detachment and aggregate formation

Abstract B093: Investigating early events of ovarian cancer transcoelomic metastasis identifies the small Rho-GTPase RHOV as an essential gene for cellular detachment and aggregate formation

Climate warming advances phenological sequences of Aesculus hippocastanum

Warming-induced shifts in plant phenology have been frequently reported in recent decades. Previous studies primarily focused on isolated phenological events; however, the entire phenological sequences of a given species were rarely examined simultaneously, limiting our knowledge about aggregate life history response to climate warming. Here, using 210,000 in situ phenological observations across 2493 European sites during 1980–2015, we examined the responses of four typical phenological events (leaf unfolding, flowering, fruiting, and leaf coloring) of Aesculus hippocastanum (horse chestnut), a common temperate tree species, to climate warming. We found that all four phenophases of A. hippocastanum advanced, i.e., the entire life cycle during the year shifted earlier with climate warming. However, the early-season phenophases (leaf unfolding and flowering) advanced faster than late-season phenophases (leaf coloring and fruiting), leading to the extension of both growing season (from leaf unfolding to leaf coloring) and reproductive season (from flowering to fruiting). The extension rate of the reproductive season was slightly greater than that of the growing season. This implied that under warming climate, more time was devoted to both vegetative growth and reproduction, particularly the latter one, in A. hippocastanum. In addition, significantly positive correlations were observed among four phenological events, particularly for pairwise consecutive events, indicating that the responses of phenological sequences to warming were highly correlated. By simultaneously studying the responses of four key phenological events to climate warming, our findings demonstrate the differences in the phenological plasticity among phenological sequences in A. hippocastanum, deepening our understanding about the impact of climate warming on life history rather than examining individual phenological events in isolation.

Abstract B012: Transcriptomic insights reveal role of BCL2 proteins in replication checkpoint inhibitor response

Abstract B012: Transcriptomic insights reveal role of BCL2 proteins in replication checkpoint inhibitor response