Broad Changes Research Articles

Interaction of serotonin/GLP-1 circuitry in a dual preclinical model for psychiatric disorders and metabolic dysfunction

Isolation of rodents throughout adolescence is known to induce many behavioral abnormalities which resemble neuropsychiatric disorders. Separately, this paradigm has also been shown to induce long-term metabolic changes consistent with a pre-diabetic state. Here, we investigate changes in central serotonin (5-HT) and glucagon-like peptide 1 (GLP-1) neurobiology that dually accompany behavioral and metabolic outcomes following social isolation stress throughout adolescence. We find that adolescent-isolation mice exhibit elevated blood glucose levels, impaired peripheral insulin signaling, altered pancreatic function, and fattier body composition without changes in bodyweight. These mice further exhibited disruptions in sleep and enhanced nociception. Using bulk and spatial transcriptomic techniques, we observe broad changes in neural 5-HT, GLP-1, and appetitive circuits. We find 5-HT neurons of adolescent-isolation mice to be more excitable, transcribe fewer copies of Glp1r (mRNA; GLP-1 receptor), and demonstrate resistance to the inhibitory effects of the GLP-1R agonist semaglutide on action potential thresholds. Surprisingly, we find that administration of semaglutide, commonly prescribed to treat metabolic syndrome, induced deficits in social interaction in group-housed mice and rescued social deficits in isolated mice. Overall, we find that central 5-HT circuitry may simultaneously influence mental well-being and metabolic health in this model, via interactions with GLP-1 and proopiomelanocortin circuitry.

A perfusion host-microbe bioreactor (HMB) system that captures dynamic interactions of secreted metabolites between epithelial cells cocultured with a human gut anaerobe.

The human microbiota impacts a variety of diseases and responses to therapeutics. Due to a lack of robust in vitro models, detailed mechanistic explanations of host-microbiota interactions cannot often be recapitulated. We describe the design and development of a novel, versatile and modular in vitro system that enables indirect coculture of human epithelial cells with anaerobic bacteria for the characterization of host-microbe secreted metabolite interactions. This system was designed to compartmentalize anaerobes and human cells in separate chambers conducive to each organism's requisite cell growth conditions. Using perfusion, fluidic mixing, and automated sample collection, the cells continuously received fresh media, while in contact with their corresponding compartments conditioned supernatant. Supernatants from each chamber were collected in a cell-free time-resolved fashion. The system sustained low oxygen conditions in the anaerobic chamber, while also supporting the growth of a representative anaerobe (Bacteroides thetaiotaomicron) and a human colonic epithelial cell line (Caco-2) in the aerobic chamber. Caco-2 global gene expression changes in response to coculture with B. thetaiotaomicron was characterized using RNA sequencing. Extensive, targeted metabolomics analysis of over 150 central carbon metabolites was performed on the serially collected supernatants. We observed broad metabolite changes in host-microbe coculture, compared to respective mono-culture controls. These effects were dependent both on sampling time and the compartment probed (apical vs. basolateral). Coculturing resulted in the depletion of several important metabolites, including guanine, uridine 5'-monophosphate, asparagine, and thiamine. Additionally, while Caco-2 cells cultured alone predominantly affected the basolateral metabolite milieu, increased abundance of 2,3-dihydroxyisovalerate and thymine on the basolateral side, occurred when the cells were cocultured with B. thetaiotaomicron. Thus, our system can capture the dynamic, competitive and cooperative processes between host cells and gut microbes.

Рецензия на монографию: Животич А. «Балканский фронт» холодной войны: СССР и югославско-албанские отношения. 1945-1968 гг. / отв. ред. А. Б. Едемский. М. – СПб.: Институт славяноведения РАН; Нестор-История, 2022. 288 с.

The reviewed publication sheds light on the history of interstate relations between the USSR, Yugoslavia, and Albania in the postwar period. The author presents these relations in the context of the broad geopolitical changes that the world underwent after the end of World War II. This monograph will be useful for specialists in the modern history of the 20th century, Slavic studies, Balkan studies, as well as all those interested in these areas of historical research.

How can psychoanalytic interpretations of political situations have effects as actions?

ABSTRACT This article examines the difficulties of making use of psychoanalytic insights to understand and influence political events. In clinical practice, it has often been possible to bring about understanding and change in patients, and in that context, immense developments in psychoanalytic theories and techniques have taken place. But there is no parallel tradition giving rise to the interpretation of unconscious political phenomena although there have been outstanding contributions of this kind by individuals, beginning with Freud's work on group psychology. There have been valuable psychoanalytic understandings of broad social changes, but effective interventions in “here and now” political situations have been few. Some examples of these include Keynes's understanding of the economic consequences of the peace of 1918 which were seen to be relevant mainly after the later peace of 1945 and Mitscherlichs' analysis in the1970s of the German people's “inability to mourn” the catastrophes of the Nazi period. The article concludes with reflections on the conditions which might facilitate effective interpretations of political situations by psychoanalysts today.

Gut microbiome is dispensable for normal respiratory function and respiratory chemoreflex

Increasing evidence indicates that gut microbiota can influence changes in respiratory homeostasis. Alterations to the gut microbiome have been hypothesized to play roles in autoimmune diseases, social behavioral deficits, and metabolic diseases such as diabetes and cardiovascular disease. We therefore aimed to determine if a model of gut dysbiosis, the absence of a gut microbiome, would result in alterations to respiratory homeostasis. After 5 days of habituation inside the Gnotobiotic animal facility, we assayed 8-week-old C57Bl/6J germ-free (GF, n=24) and specific-pathogen-free (SPF, n=24) control mice under normoxic (21% O2,79% N2) conditions, followed by a hypercapnic challenge (5% CO2, 21% O2, 74% N2) and hypoxic challenge (10% O2, 90% N2). Importantly, this germfree model does not involve treatment with high-dose antibiotics, which have been implicated in neurotoxic sequela. Whole-body flow through plethysmography was used to monitor respiratory function and metabolic demand in conscious and unrestrained animals. Recordings were interrogated using our newly published open-source software, Breathe Easy, for breath cycle duration, respiratory rate (Vf), tidal volume (VT), minute ventilation (VE), oxygen consumption (VO2), and minute ventilation normalized by oxygen consumption (VE/VO2) during room air, initial hypoxic and hypercapnic exposures, and steady-state hypoxic and hypercapnic respiratory responses. A linear mixed effects model with a Tukey post-hoc test was performed to test for significant differences wherein respiratory outcomes were dependent variables, and strain and sex were independent variables. In male mice, there was a significant decrease in breath cycle duration during room air in GF compared to SPF controls. We also saw a significant decrease in ventilatory equivalents of oxygen in the initial hypoxic response in GF mice compared to SPF controls in males, but not in the steady-state of hypoxic exposure. Finally, we note a significant increase in oxygen consumption in females during room air measurements. Of note, female mice showed significant irregularity in all respiratory parameters except oxygen consumption whereas males only showed significant irregularity in breath cycle duration during hypoxic steady-state and the hypercapnic steady-state, and tidal volume in the initial hypoxic response. While there are significant changes, it remains to be determined what the underlying mechanisms are and how they may play a contributory role in pathophysiologies co-morbid with gut microbiome dysregulation. Taken together, these results suggest that the gut microbiome is largely dispensable for normal respiratory function and respiratory chemoreflexes in adult mice and that the lack of a gut microbiome, a model of gut dysbiosis, does not result in broad significant changes in respiratory homeostasis. NIH: 1F32HL160073-01A1, R01HL130249 44617-S4. BCM McNair Scholar Program, March of Dimes Basil O'Connor Research Award, Parker B. Francis Fellowship, CJ Foundation for SIDS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Modelling atopic dermatitis in healthy human skin for the characterization of topical compounds.

Suitable human models for the development and characterization of topical compounds for inflammatory skin diseases such as atopic dermatitis are not readily available to date. We describe here the development of a translational model involving healthy human skin mimicking major aspects of AD and its application for the characterization of topical Janus kinase inhibitors. Full thickness human abdominal skin obtained from plastic surgery stimulated invitro with IL4 and IL13 shows molecular features of AD. This is evidenced by STAT6 phosphorylation assessed by immunohistochemistry and analysis of skin lysates. Broad transcriptome changes assessed by AmpliSeq followed by gene set variation analysis showed a consistent upregulation of gene signatures characterizing AD in this model. Topical application of experimental formulations of compounds targeting the JAK pathway to full thickness skin normalizes the molecular features of AD induced by IL4 and IL13 stimulation. The inhibitory effects of topical JAK inhibitors on molecular features of AD are supported by pharmacokinetic analysis. The model described here is suited for the characterization of topical compounds for AD and has the potential to be extended to other inflammatory skin diseases and pathophysiological pathways.

Abstract 3005: Transgenerational Impact Of E-cigarette Nicotine Vaping On Abdominal Aortic Aneurysm

Background: Smoking and family history are major risk factors for abdominal aortic aneurysm (AAA). Smoking is a powerful modulator of DNA methylation, and nicotine can cause heritable epigenetic alterations in animals and humans. We found that nicotine infusion and e-cigarette (e-cig) vaping augment murine AAA, and that parental nicotine infusion augments model AAA in offspring, altering tissue DNA methylation patterns. Hypothesis: We investigated the effects of maternal e-cig vaping in mice on their offspring’s experimental AAA risk, and transgenerational DNA methylation. Methods: Two treatment arms were employed: 1) pre-fertilization or 2) peri-natal. Female ApoE-/- or C57BL6 mice (F0) were exposed to e-cig nicotine (24 mg/ml) puffs, 9 sec/min, 1 hour/day (or room air). Arm 1: treated 28 days, then mated to untreated controls. Arm 2: mated after 1 week of e-cig, then maintained on treatment until gestation was complete. Aortic tissue of 10-week-old F1 offspring was evaluated using RRBS-Seq DNA methylation analysis. Parallel offspring underwent angiotensin-II infusion (1μg/kg/min; ApoE-/-) or elastase infusion (2U/ml for 5 min at 120 mmHg; C57) to induce AAA. Aneurysm growth was ultrasound tracked over 28 days. Results: Maternal vape exposure altered aortic DNA methylation in offspring, with numerous differentially methylated regions (DMRs; q<0.1). Hundreds of these DMRs were located in the same genes previously identified in offspring of nicotine-infused mice (see Background). Vaping altered offspring aortic methylation patterns in AAA-related genes, including miRNAs. DMR pathway analysis was enriched in transcription factors. Further, many DMRs were located in genes harboring risk loci for human AAA from our recent collaborative publication. Maternal e-cig exposure augmented AAA size in both models, arms, and genders (p<0.05). AAA incidence and mortality were increased in ApoE-/- in both genders and arms. Effects were most significant in males. Conclusions: E-cig nicotine exposure augments experimental AAA growth in multiple models across generations. These effects are accompanied by broad aortic epigenetic changes, including in key AAA modulator genes, with enrichment in transcription factors that target known AAA-related genes.

Analysis of Land Use and Land Cover Change Detection for Indore District of Malwa Plateau Region Using Supervised Machine Learning

The main aim of this work is to find out LULC classes for the Indore region. For the last seven years, Indore has been crowned the cleanest city in India according to the latest ranking of 2023. In the Indian state of Madhya Pradesh, the city and district of Indore are situated on the southern edge of the Malwa plateau. The municipalities of the Indore district majorly cover Manpur, Depalpur, Goutampura, Mhow, Hatod, Betma, Rau and Sanwer, with an area of approximately 3900 square kilometers. In contrast, Indore covers a land area of approximately 530 square kilometres. It is in charge of the nation’s slow but steady industrialization and population growth found in the last three decades. The city was much smaller and had a far smaller population thirty years ago. However, to evaluate the changes and decide on Indore city's future planning, Indore has taken over responsibility for the city's economic activities in recent years. New appropriate patterns should be recommended based on local factors like topography characteristics. The satellite image with multiple spectrums was used for the investigation. ArcGIS is based on pixel-by-pixel supervised classification using the maximum likelihood approach of Landsat satellite images from 2003 and 2023. The ground area, agriculture, and urbanization are linked to the LULC features. The various categories of classified land use and land cover features include the area of built-up regions, water bodies, cropland, forest, and barren land taken to predict the broad changes. Remotely sensed Landsat 5 images of 2003 and 8 images of 2023 were utilized to identify changes to accomplish this goal. This work clarifies the comparison of LULC classes for the Indore region.

Ribosome subunit attrition and activation of the p53–MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the ‘WIN’ site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

Monitoring Change and Recovery of an Embayed Beach in Response to Typhoon Storms Using UAV LiDAR

The monitoring of beach topographical changes and recovery processes under typhoon storm influence has primarily relied on traditional techniques that lack high spatial resolution. Therefore, we used an unmanned aerial vehicle light detection and ranging (UAV LiDAR) system to obtain the four time periods of topographic data from Tantou Beach, a sandy beach in Xiangshan County, Zhejiang Province, China, to explore beach topography and geomorphology in response to typhoon events. The UAV LiDAR data in four survey periods showed an overall vertical accuracy of approximately 5 cm. Based on the evaluated four time periods of the UAV LiDAR data, we created four corresponding DEMs for the beach. We calculated the DEM of difference (Dod), which showed that the erosion and siltation on Tantou Beach over different temporal scales had a significant alongshore zonal feature with a broad change range. The tidal level significantly impacted beach erosion and siltation changes. However, the storm surge did not affect the beach area above the spring high-tide level. After storms, siltation occurred above the spring high-tide zone. This study reveals the advantage of UAV LiDAR in monitoring beach changes and provides novel insights into the impacts of typhoon storms on coastal topographic and geomorphological change and recovery processes.

Finding modernity in England's past: Social anthropology and the remaking of social history in Britain, 1959–77

British historians drew on anthropological exemplars to remake social history between 1959 and 1977. Eric Hobsbawm's ‘primitive rebels’, Peter Laslett's World We Have Lost, Keith Thomas’s studies of witchcraft, and E. P. Thompson's ‘moral economy’ were all inspired by contemporary social anthropology, and they transformed historians’ understanding of the past. Reconstructing this moment of cross-disciplinary research contributes to our understanding of broader changes in the mid-century human sciences. This was a moment of grand theorizing about ‘modernization’, capitalism, and industrialization. Social historians responded to these concerns by drawing analogies between the past and the ethnographic present. The result was a number of hugely influential studies of social change that posed new questions to those seeking to create abstract models of modernization out of the English past.

Multi-omic profiling reveals the endogenous and neoplastic responses to immunotherapies in cutaneous T cell lymphoma

Cutaneous Tcell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic Tcells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA+CD39+ Tcells. We develop an unbiased multi-omic profiling approach enabling discovery of immune modules stratifying patients. We identify an enrichment of activated regulatory CLA+CD39+ Tcells in non-responders and activated cytotoxic CLA+CD39+ Tcells in leukemic patients. Our results provide insights into the effects of immunotherapy in CTCL patients and a generalizable framework for multi-omic analysis of clinical trials.

SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.

Dysregulated metabolism of bioactive sphingolipids, including ceramides and sphingosine-1-phosphate, has been implicated in cardiovascular disease, although the specific species, disease contexts, and cellular roles are not completely understood. Sphingolipids are produced by the serine palmitoyltransferase enzyme, canonically composed of 2 subunits, SPTLC1 (serine palmitoyltransferase long chain base subunit 1) and SPTLC2 (serine palmitoyltransferase long chain base subunit 2). Noncanonical sphingolipids are produced by a more recently described subunit, SPTLC3 (serine palmitoyltransferase long chain base subunit 3). The noncanonical (d16) and canonical (d18) sphingolipidome profiles in cardiac tissues of patients with end-stage ischemic cardiomyopathy and in mice with ischemic cardiomyopathy were analyzed by targeted lipidomics. Regulation of SPTLC3 by HIF1α under ischemic conditions was determined with chromatin immunoprecipitation. Transcriptomics, lipidomics, metabolomics, echocardiography, mitochondrial electron transport chain, mitochondrial membrane fluidity, and mitochondrial membrane potential were assessed in the cSPTLC3KO transgenic mice we generated. Furthermore, morphological and functional studies were performed on cSPTLC3KO mice subjected to permanent nonreperfused myocardial infarction. Herein, we report that SPTLC3 is induced in both human and mouse models of ischemic cardiomyopathy and leads to production of atypical sphingolipids bearing 16-carbon sphingoid bases, resulting in broad changes in cell sphingolipid composition. This induction is in part attributable to transcriptional regulation by HIF1α under ischemic conditions. Furthermore, cardiomyocyte-specific depletion of SPTLC3 in mice attenuates oxidative stress, fibrosis, and hypertrophy in chronic ischemia, and mice demonstrate improved cardiac function and increased survival along with increased ketone and glucose substrate metabolism utilization. Depletion of SPTLC3 mechanistically alters the membrane environment and subunit composition of mitochondrial complex I of the electron transport chain, decreasing its activity. Our findings suggest a novel essential role for SPTLC3 in electron transport chain function and a contribution to ischemic injury by regulating complex I activity.

Changing Nature of the European Union - Turkey Relations: From Civilizational Project to Transactional Cooperation

Turkey’s ambition to be anchored in the European integration process is one of the oldest and most challenging priorities of its foreign policy. As a symbolic coincidence, the centenary of the Republic of Turkey overlaps with the 60th anniversary of its association relationship with the then European Economic Community (EEC) during when both sides have experienced frequent fluctuations in their bilateral relations. In that sense, the idea of change has always embedded in Turkey-European Union (EU) relations corresponding to much broader changes in Turkey’s foreign policy. This study is aware of the fact that focusing on one side will provide only a partial explanation of variations in the EU-Turkey relations and aims to present the drivers of change in their mutual relations not only by focusing on the actions and inactions of the successive Turkish governments but also by paying attention to the changes in the EU’s and its member states’ policies towards Turkey. This study adopts literature review and tries to answer how Turkey’s EU policy has transformed in the last 60 years by analysing historical turning points in this period and their implications for the ongoing relations. Based on this historical analysis, this study argues that the relationship between the EU and Turkey, which has been becoming increasingly distant from each other, has lost the initial civilisational spirit and turned into a patronage symbolised by ad-hoc transactional agreement/s.

Preparation and characterization of eicosane-paraffin/expanded graphite/polyurethane as form-stable composite phase change materials with wide phase change temperature range

Phase change materials (PCMs) with wide phase change temperature range, high latent heat, good thermal conductivity, and shape stability are essential for applications such as solar energy conservation and thermal management of electronic devices. Form-stable composite PCMs (FSCPCMs) with a broad phase change temperature range of 18–65 °C were successfully developed by using a mixture of eicosane and paraffin mixture along with cross-linking polyurethane as PCM, expanded graphite as thermally conductive filler and supporting material. The prepared FSCPCMs demonstrated excellent thermal stability and thermal conductivity with a latent heat up to 142.5 J/g. In conclusion, the synthesized FSCPCMs exhibit promising potential for practical applications in thermal energy storage.

Say Nope to the Pope: performance and resistance in the creative interventions during the 2018 papal visit to Ireland

ABSTRACT In September 1979, the newly elected head of the Catholic Church, Pope John Paul II, made a historic pastoral visit to Ireland where he celebrated an open-air mass in Dublin’s Phoenix Park to an estimated 1,250,000 people, a third of the country’s population. In August 2018, Pope Francis returned to Ireland, though the second papal visit was met with a series of protests and a lower-than-expected turn-out at the public mass in Phoenix Park. In the intervening years Ireland underwent broad social changes and the credibility of the Catholic Church, once the bedrock of morality in Ireland, was eroded by scandals revealing the depths of clerical sex abuse and abuse in Catholic-run institutions. This article considers the creative protests and interventionist actions that marked the 2018 Papal visit, using Judith Butler’s Notes Toward A Performative Theory of Assembly (2015) to think through these public actions. Focusing specifically on Say Nope to the Pope and the associated events of Stand 4 Truth, it explores these public performances of protest grounded in solidarity and resistance.

Early life phenobarbital exposure dysregulates the hippocampal transcriptome.

Introduction: Phenobarbital (PB) and levetiracetam (LEV) are the first-line therapies for neonates with diagnosed seizures, however, a growing body of evidence shows that these drugs given during critical developmental windows trigger lasting molecular changes in the brain. While the targets and mechanism of action of these drugs are well understood-what is not known is how these drugs alter the transcriptomic landscape, and therefore molecular profile/gene expression during these critical windows of neurodevelopment. PB is associated with a range of neurotoxic effects in developing animals, from cell death to altered synaptic development to lasting behavioral impairment. LEV does not produce these effects. Methods: Here we evaluated the effects of PB and Lev on the hippocampal transcriptome by RNA sequencing. Neonatal rat pups were given a single dose of PB, Lev or vehicle and sacrificed 72h later-at time at which drug is expected to be cleared. Results: We found PB induces broad changes in the transcriptomic profile (124 differentially expressed transcripts), as compared to relatively small changes in LEV-treated animals (15 transcripts). PB exposure decreased GABAergic and oligodendrocyte markers pvalb and opalin, and increased the marker of activated microglia, cd68 and the astrocyte- associated gene vegfa. These data are consistent with the existing literature showing developmental neurotoxicity associated with PB, but not LEV. Discussion: The widespread change in gene expression after PB, which affected transcripts reflective of multiple cell types, may provide a link between acute drug administration and lasting drug toxicity.

Climate change science is evolving toward adaptation and mitigation solutions

AbstractSynthesizing the extensive and ever‐growing climate change literature is becoming increasingly challenging using conventional review processes, yet is crucial to understand key trends, including knowledge and policy related gaps, managing widespread impacts, and prioritizing future efforts. Here, we employ a systematic approach to interrogate ~130,000 international peer‐reviewed climate change articles published between 1990 and 2021. We examine the time–space evolution of research topics and international collaborations, providing insights into broad scale climate change research themes, how they are developed and/or are interconnected. Our analyses indicate that significant thematic adjustments have occurred over the past three decades. Whilst all major areas of climate research have grown in output metrics, there has been a relative shift from understanding the physical science basis toward evaluating climate change impacts, adaptation, and mitigation. There has also been a significant internationalization of climate research with the ratio of international over domestic research increasing from 0.05 in 1990 to nearly 0.60 in 2021. These findings reveal a growing need for collective and coupled adaptation‐mitigation actions to address climate change. The repeatable method and overall results presented herein can help to complement existing large‐scale literature assessments, such as future IPCC reports.This article is categorized under: Climate, History, Society, Culture > Disciplinary Perspectives Integrated Assessment of Climate Change > Methods of Integrated Assessment of Climate Change

Abstract 2694: The role of innate lymphoid cells and innate like T cells in hepatocellular carcinoma

Abstract The major focus of cancer immunotherapy has been on conventional T cells due to their unique recognition of specific peptide antigens. Despite advances in the cancer immunotherapy field, including the use of atezolizumab and bevacizumab as first-line therapy for unresectable hepatocellular carcinoma (HCC), the overall mortality rate of HCC continues to rise. Innate lymphoid cells (ILC) and innate-like T cells (ILTC) are broadly categorized within the innate lymphoid population as playing an important role in inflammation, tissue repair and immune tolerance. Their ability to react rapidly to stimulants in their local tissue environment as well as to recruit and activate a variety of other immune cells makes these cells attractive targets for anti-tumor therapy. However, previous studies looking at ILCs and ILTCs in cancer have revealed both pro- and anti-tumor functions. Furthermore, the complex interplay between these cell populations in the tumor microenvironment is not well understood, particularly over the natural course of tumor development. In this study, we aim to better elucidate the role of ILC and ILTC populations in HCC progression in terms of both their kinetics and role as potential therapeutic targets. We performed hydrodynamic tail vein injections in mice with two different plasmid combinations to alter expression of commonly mutated oncogenes and tumor suppressors in human HCC (MYC;TP53 and MYC;CTNNB1). Histologic analysis of the livers was performed to determine appropriate time points to assess ILC and ILTC populations. We then designed a comprehensive 29-plex spectral flow panel to assess broad kinetic changes in the frequency of ILC, ILTC, and conventional T cell populations. We show that in early time points (4-7 days post-injection) when neoplastic transformation of hepatocytes has already occurred, mucosal-associated invariant T (MAIT) cells, group 1 ILCs, ILC2s, and ILC3s expand in frequency for both tumor models. Cytokine analysis shows a generalized decreased trend across timepoints in effector cytokine production in MAITs and group 1 ILCs, suggesting gradual dysfunction over time. Taken together, these preliminary findings show that ILC and ILTC populations expand early during tumor progression but gradually decrease in functionality with tumor progression. Citation Format: Patrick Huang, Benjamin Ruf, Rajiv Trehan, Dana Soika, Chi Ma, Tim F. Greten, Firouzeh Korangy. The role of innate lymphoid cells and innate like T cells in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2694.