Molecular Adaptations Research Articles

Abstract A012: Aging drives TNBC lung metastasis dependency on FGFR-triggered metabolic reprogramming exposing an age-induced liability with therapeutic potential

Abstract The clinical manifestation of metastasis in a vital organ is the final stage of breast cancer progression and the main culprit of breast cancer related mortality. This remain especially problematic in the case of triple negative breast cancer (TNBC), the most aggressive type of breast cancer, often diagnosed in its metastatic form and for which chemotherapies are still the major therapeutic option. Typically, TNBC is seen as a disease of younger women, however, 20% of TNBCs occur in patients aged 65 and older, whose prognosis is equally staggering. Unfortunately, due to co-morbidities, tolerability of chemotherapies, as well as severe reduction in quality of life, majority of women above age 65 can’t or decide not to receive chemotherapy ultimately cutting their lives short. Metastatic outgrowth is largely dictated by the ability of TNBC disseminated cancer cells (DCCs) to thrive distal organs and is largely dependent on the physiology of the specific organs. However, how the aging process, a major driver of changes in organismal physiology, affects the interaction between the host organ and TNBC DCCs remains unknown. Here, we adapted several traditional syngeneic models of TNBC metastasis to old mice of different strains and coupled with RNA-seq to unveil molecular adaptations of TNBC DCCs to the aging lung. We show that the changes that occur in the lung with aging drives an increase in mitochondrial fitness in TNBC DCCs, an adaptation that is necessary for metastasis to thrive in the old lung environment. Mechanistically, our data show that the expression of FGF19, a gut hormone not normally expressed in TNBC DCCs, drives this increase in mitochondrial fitness in the old lung through an autocrine signaling axis impinging on activation of FGF-19 cognate receptor family, FGFRs. Inhibition of FGF19-FGFR signaling using an FDA- approved FGFR inhibitor not only blocks the age-induced increase in mitochondrial fitness but also effectively abolishes lung metastasis in old, but not in young, immune competent and immune compromised mice. We traced this to age-specific metastatic adaptation of TNBC lung metastasis to the increase in bile acids, the canonical regulators of FGF19 expression, in the old lung environment. Together, our work demonstrates an important contribution of age-driven metabolic reprogramming of the host to the traits that enable metastasis to thrive in the lung and provides rationale for the use of FDA-approved FGFR inhibitors for the treatment of breast cancer lung metastasis in the most vulnerable of stage IV metastatic TNBC patients, the elderly. Citation Format: Stanislav Drapela, Shiun Chang, Rojan Chimeh Rad, Vanessa Rubio, Didem Ilter, Paulo Rodriguez, Ana P. Gomes. Aging drives TNBC lung metastasis dependency on FGFR-triggered metabolic reprogramming exposing an age-induced liability with therapeutic potential [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A012.

Abstract 4129195: Mechanisms of Healthy Aging in the Prevention of Atrial Fibrillation

Introduction: Atrial Fibrillation (AF) is the most frequent cardiac arrhythmia. AF can lead to severe complications such as myocardial infarction, strokes, and sudden death. With 70% of AF patients aged 65 and older, aging stands as the major risk factor for AF. Our group have recently contributed to reveal that old Wistar rats (20 months) are more susceptible to AF than younger rats (5 months). Interestingly, Lou/c/jall (LOU) rats, a model of healthy aging derived from Wistar rats, can live up to ~35 months old (equivalent to 100 human years). LOU rats have been identified as resistant to age-related diseases such as obesity, hypertension, and neurodegenerative disorders, which are major risk factors for AF. However, the susceptibility of LOU rats to AF have never been reported. Hypothesis: LOU rats may carry specific molecular adaptations conferring resistance to age-related cardiac remodeling and low AF vulnerability. Objectives: Characterize the vulnerability of very old LOU rats (32 months) to AF compared to old Wistar rats (22 months). Determine the atrial inflammatory profile of LOU rats and identify the molecular adaptations that may explain their resistance to AF Methods: Male and Female rats were divided into five groups: LOU and Wistar rats of 5 months (young), 20 months (old), and 32 months (very old: LOU/c rats only). AF inducibility was assessed in vivo using transesophageal electrophysiological study and cardiac structure and function were analyzed by in vivo echocardiography. Atrial electrical conduction was examined using ex vivo optical mapping. Histological analyses were performed to assess atrial fibrosis. Additionally, immunoblot analysis, qPCR, and RNA sequencing were employed to investigate the levels of biomarkers involved in atrial inflammation and fibrosis. Result: Old Wistar rats were more vulnerable to AF than young rats. Old and very old LOU were significantly more resistant to AF than old Wistar animals. LOU rats’ low susceptibility to AF was accompanied with absence of cardiac structural and functional remodeling and low levels of atrial fibrosis compared to old Wistar. Additionally, advanced age did not affect LOU rats’ atrial electrical conduction properties as compared to old Wistar rats. Conclusion: Promotion of healthy aging conditions mimicking LOU rats’ resistance to cardiac remodeling and reduction of atrial fibrosis may contribute to prevent AF in subjects with pathological aging.

Hypoxia stress: plant's sensing, responses, and tolerance mechanisms.

Oxygen (O2) is an inhibiting factor for plant growth and development in submerged and flooding environments. Plants experience different O2 concentrations, such as normoxia, hypoxia, and anoxia, which can change over space and time. Plants have evolved various morphological, physiological, and biochemical adaptations to withstand low O2 stress, many of which have been well investigated. This review provides a detailed analysis of how plants respond to hypoxia, a significant stress factor primarily caused by flooding. Hypoxia affects plants at various cellular, developmental, and environmental levels. This review highlights genetic, molecular, and metabolic adaptations crops employ to cope with O2 deficiency. The roles of various transcription factors (TFs) and gene regulation mechanisms in enabling plants to modulate their physiological responses under hypoxic conditions are notable. The review also identifies a significant gap in research on plant responses during reoxygenation, the phase of returning to normal O2 levels, especially under natural lighting conditions. This transition poses ROS generation and photoinhibition challenges, affecting plant recovery post-hypoxia. We discuss various strategies to enhance plant hypoxia tolerance, including traditional breeding, genetic modification, and grafting techniques. It emphasizes integrating these approaches with a comprehensive understanding of hypoxia sensing and response mechanisms. We underscore the complexity of plant adaptations to hypoxia and the need for continued research in this field, especially in the face of global climate change. This is vital for developing sustainable agricultural practices and ensuring future food security.

Immune defense adaptation of Strauchbufo raddei population in heavy metal polluted area: Insights from developmental and environmental perspectives

The adjustment of immune defense mechanisms is a crucial aspect of biological adaptation to stressful environments. Amphibians, with their unique metamorphic process, experience distinct life stages and exhibit diverse immune defense components. While previous studies have focused on specific immune changes during particular life stages under stress, this research addresses a critical gap by exploring the adaptive immune defense strategies of Strauchbufo raddei in heavy metal-polluted environments. We conducted laboratory experiments, exposing offspring from both polluted and unpolluted areas to control and heavy metal treatments, while continuously monitoring changes in immune components during key metamorphic stages. Notably, we examined the role of the skin microbiome, a crucial but often overlooked barrier against pathogens. The results indicated that individuals from polluted areas exhibited some tolerance to heavy metal exposure, though overall immune function remained diminished. During metamorphosis, when immune defenses are most vulnerable, the skin microbiome rapidly enriched beneficial bacteria, preventing pathogenic colonization and playing a pivotal role in maintaining immune defense in contaminated environments. Moreover, our research highlights energy allocation strategies involving corticosterone and body fat content, enabling populations to maintain development despite immune compromise. The immune adaptations observed may be fixed through genetic assimilation, suggesting a rapid evolutionary response to environmental stress. However, this reduces phenotypic plasticity, making populations more vulnerable to future environmental changes. This study provides key insights into the survival strategies of amphibian populations in heavy metal-contaminated areas, laying the foundation for future research on molecular and evolutionary adaptations.

Comparative Analysis of Two Soybean Cultivars Revealed Tolerance Mechanisms Underlying Soybean Adaptation to Flooding

Flooding stress poses a significant challenge to soybean cultivation, impacting plant growth, development, and ultimately yield. In this study, we investigated the responses of two distinct soybean cultivars: flooding-tolerant Nanxiadou 38 (ND38) and flooding-sensitive Nanxiadou 45 (ND45). To achieve this, healthy seedlings were cultivated with the water surface consistently maintained at 5 cm above the soil surface. Our objective was to elucidate the physiological and molecular adaptations of the two cultivars. Under flooding stress, seedlings of both cultivars exhibited significant dwarfing and a notable decrease in root length. While there were no significant differences in the dry weight of aboveground shoots, the dry weight of underground shoots in ND38 was strikingly decreased following flooding. Additionally, total chlorophyll content decreased significantly following flooding stress, indicating impaired photosynthetic performance of the cultivars. Moreover, malondialdehyde (MDA) levels increased significantly after flooding, particularly in the ND45 cultivar, suggesting heightened oxidative stress. Expression analysis of methylation and demethylation genes indicated that MET1 and DME play crucial roles in response to flooding stress in soybeans. Meanwhile, analysis of the hemoglobin family (GLBs), aquaporin family (AQPs), glycolytic pathway-related genes, and NAC transcription factor-related genes identified GLB1-1 and GLB1-2, GLB2-2, PIP2-6, PIP2-7, TIP2-2, TIP4-1, TIP5-1, Gm02G222400 (fructose-bisphosphate aldolase), Gm19G017200 (glucose-6-phosphate isomerase), and Gm04G213900 (alcohol dehydrogenase 1) as key contributors to flooding tolerance in both soybean cultivars. These findings provide crucial insights into the physiological and molecular mechanisms underlying flooding tolerance in soybeans, which could guide future molecular breeding strategies for the development of flooding-tolerant soybean cultivars.

The 24-hour molecular landscape after exercise in humans reveals MYC is sufficient for muscle growth.

A detailed understanding of molecular responses to a hypertrophic stimulus in skeletal muscle leads to therapeutic advances aimed at promoting muscle mass. To decode the molecular factors regulating skeletal muscle mass, we utilized a 24-h time course of human muscle biopsies after a bout of resistance exercise. Our findings indicate: (1) the DNA methylome response at 30 min corresponds to upregulated genes at 3 h, (2) a burst of translation- and transcription-initiation factor-coding transcripts occurs between 3 and 8 h, (3) changes to global protein-coding gene expression peaks at 8 h, (4) ribosome-related genes dominate the mRNA landscape between 8 and 24 h, (5) methylation-regulated MYC is a highly influential transcription factor throughout recovery. To test whether MYC is sufficient for hypertrophy, we periodically pulse MYC in skeletal muscle over 4 weeks. Transient MYC increases muscle mass and fiber size in the soleus of adult mice. We present a temporally resolved resource for understanding molecular adaptations to resistance exercise in muscle ( http://data.myoanalytics.com ) and suggest that controlled MYC doses influencethe exercise-related hypertrophic transcriptional landscape.

Short-term exercise counteracts accelerated ageing impacts on physical performance and liver health in mice.

Senescence impairs liver physiology, mitochondrial function and circadian regulation, resulting in systemic metabolic dysregulation. Given the limited research on the effects of combined exercise on an ageing liver, this study aimed to evaluate its impact on liver metabolism, circadian rhythms and mitochondrial function in senescence-accelerated mouse-prone 8 (SAMP8) and senescence-accelerated mouse-resistant 1 (SAMR1) mice. Histological, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting analyses were conducted, supplemented by transcriptomic data sets and AML12 hepatocyte studies. Sedentary SAMP8 mice exhibited decreased muscle strength, reduced mitochondrial complex I levels and increased lipid droplet accumulation. In contrast, combined exercise mitigated muscle strength loss, upregulated proteins involved in mitochondrial complexes (CIII, CIV, CV) and increased Bmal1 messenger RNA (mRNA) expression in the liver. These molecular adaptations are associated with healthier liver phenotypes and may influence metabolic function and cellular longevity. Notably, elevated lipid content in aged mice was reduced post-exercise, indicating liver benefits even after a relatively short intervention. The combined exercise regimen did not improve aerobic capacity, likely due to the low volume and brief duration of running. Moreover, no significant effects were observed in SAMR1 mice, possibly because the training intensity was insufficient for younger, healthier animals. These findings underscore the potential of combined strength and endurance exercise to attenuate age-related liver dysfunction, particularly in ageing populations.

Salt Tolerance in Sugar Beet: From Impact Analysis to Adaptive Mechanisms and Future Research.

The continuous global escalation of soil salinization areas presents severe challenges to the stability and growth of agricultural development across the world. In-depth research on sugar beet (Beta vulgaris L.), an important economic and sugar crop with salt tolerance characteristics, is crucial for to determine its salt-tolerance mechanisms, which has important practical implications for production. This review summarizes the multifaceted effects of salt stress on sugar beet, ranging from individual plant responses to cellular and molecular adaptations. Sugar beet exhibits robust salt-tolerance mechanisms, including osmotic regulation, ion balance management, and the compartmentalization of toxic ions. Omics technologies, including genomics, transcriptomics, proteomics, post-translational modification omics and metabolomics, have played crucial roles in elucidating these mechanisms. Key genes and pathways involved in salt tolerance in sugar beet have been identified, paving the way for targeted breeding strategies and biotechnological advancements. Understanding these mechanisms not only enhances our knowledge of sugar beet's adaptation strategies but also provides insights for improving salt tolerance in other crops. Future studies should focus on analyzing gene expression changes in sugar beet under salt stress to gain insight into the molecular aspects of its salt-tolerance mechanisms. Meanwhile, the effects of different environmental conditions on sugar beet adaptation strategies should also be investigated to improve their growth potential in salinized soils.

A functionally augmented carbohydrate utilization locus from herbivore gut microbiota fueled by dietary β-glucans

Gut microbiota members from the Bacteroidota phylum play a pivotal role in mammalian health and metabolism. They thrive in this diverse ecosystem due to their notable ability to cope with distinct recalcitrant dietary glycans via polysaccharide utilization loci (PULs). Our study reveals that a PUL from an herbivore gut bacterium belonging to the Bacteroidota phylum, with a gene composition similar to that in the human gut, exhibits extended functionality. While the human gut PUL targets mixed-linkage β-glucans specifically, the herbivore gut PUL also efficiently processes linear and substituted β-1,3-glucans. This gain of function emerges from molecular adaptations in recognition proteins and carbohydrate-active enzymes, including a β-glucosidase specialized for β(1,6)-glucosyl linkages, a typical substitution in β(1,3)-glucans. These findings broaden the existing model for non-cellulosic β-glucans utilization by gut bacteria, revealing an additional layer of functional and evolutionary complexity within the gut microbiota, beyond conventional gene insertions/deletions to intricate biochemical interactions.

Carotenoids dispersed in gypsum rock as a result of algae adaptation to the extreme conditions of the Atacama Desert

The high-altitude pre-Andean region of the Atacama Desert is characterized by its stark volcanic rock formations and unique hydrothermal gypsum outcrops (gypcrete) that it hosts. This study delves into the biomolecular composition of the endolithic phototrophic microbes that thrive within these gypcretes. Using advanced Raman spectroscopy techniques, including Raman imaging (complemented by microscopic and 3D microscopic observations), herein we unveil new insights into the adaptive strategies of these gypsum-inhabiting algae. Our Raman imaging results provide a detailed chemical map of carotenoids associated with microbial colonization. This map reveals a significant gradient in pigment content, highlighting a critical survival mechanism for algae and cyanobacteria in this polyextreme environment. Intriguingly, we detected signals for carotenoids not only in the algae-colonized layer, but also deeper within the gypsum matrix - indicating pigment migration following cell disruption. In addition, we conducted an in-depth analysis of individual algal cells from the Trebouxiaceae family, noting their color variations from green to orange, plus describing the spectral differences in detail. This investigation identified in-vivo pigments (carotenoids, chlorophyll) and lipids at the cellular level, offering a comprehensive view of the molecular adaptations enabling life in one of the Earth’s most extreme habitats.

Striatal cell-type-specific molecular signatures reveal therapeutic targets in a model of dystonia.

Striatal dysfunction is implicated in many forms of dystonia, including idiopathic, inherited and iatrogenic dystonias. The striatum is comprised largely of GABAergic spiny projection neurons (SPNs) that are defined by their long-range efferents. Direct SPNs (dSPNs) project to the internal globus pallidus/substantia nigra reticulata whereas indirect pathway SPNs (iSPNs) project to the external pallidum; the concerted activity of both SPN subtypes modulates movement. Convergent results from genetic, imaging and physiological studies in patients suggest that abnormalities of both dSPNs and iSPNs contribute to the expression of dystonia, but the molecular adaptations underlying these abnormalities are not known. Here we provide a comprehensive analysis of SPN cell-type-specific molecular signatures in a model of DOPA-responsive dystonia (DRD mice), which is caused by gene defects that reduce dopamine neurotransmission, resulting in dystonia that is specifically associated with striatal dysfunction. Individually profiling the translatome of dSPNs and iSPNs using translating ribosome affinity purification with RNA-seq revealed hundreds of differentially translating mRNAs in each SPN subtype in DRD mice, yet there was little overlap between the dysregulated genes in dSPNs and iSPNs. Despite the paucity of shared adaptations, a disruption in glutamatergic signaling was predicted for both dSPNs and iSPNs. Indeed, we found that both AMPA and NMDA receptor-mediated currents were enhanced in dSPNs but diminished in iSPNs in DRD mice. The pattern of mRNA dysregulation was specific to dystonia as the adaptations in DRD mice were distinct from those in parkinsonian mice where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. We leveraged the unique molecular signatures of dSPNs and iSPNs in DRD mice to identify biochemical mechanisms that may be targets for therapeutics, including LRRK2 inhibition. Administration of the LRRK2 inhibitor MLi-2 ameliorated the dystonia in DRD mice suggesting a novel target for therapeutics and demonstrating that the delineation of cell-type-specific molecular signatures provides a powerful approach to revealing both CNS dysfunction and therapeutic targets in dystonia.

VascuFit: Aerobic exercise improves endothelial function independent of cardiovascular risk: A randomized-controlled trial.

Background and aimsEndothelial dysfunction predicts elevated cardiovascular (CV) risk in healthy individuals. Aerobic exercise reduces endothelial dysfunction in part by improving CV risk factors. Yet, this explains less than 50% of the effect and a direct influence of exercise training on the endothelium is discussed as possible contributor. The VascuFit study applied non-linear periodized aerobic exercise (NLPE) training to assess its multilevel effects on endothelial function including potential epigenetic endothelial modifications by circulating micro-ribonucleic acids (endomiRs). MethodsSedentary adults with elevated CV risk between 40-60 years were randomized 2:1 and engaged in an eight-week ergometer-based NLPE training (n=30) or received standard exercise recommendations (n=14). Macro-, microvascular, cellular and molecular adaptations were assessed via brachial-arterial flow-mediated dilation (baFMD), static retinal vessel analysis (SVA), flow cytometry, and endomiRs regulating key pathways of endothelial function. Statistics included ANCOVA, Principal Component Analysis (PCA), and regression analyses. ResultsbaFMD improved by 2.38% (CI:0.70-4.06, p=0.007) independent of CV risk, whereas SVA parameters and circulating endothelial (progenitor) cells did not significantly change in the NLPE group. The mean distance between baseline and follow-up PCA loadings of the endomiR dataset explaining 44.2% of dataset variability was higher in the NLPE-group compared to the control group (2.71±2.02 vs. 1.65±0.93). However, regression analyses showed no evidence of endomiRs explaining the improvement of baFMD. ConclusionsThe improvement of macrovascular endothelial function by aerobic exercise training was independent from CV risk factors. Increased heterogeneity among endomiRs did not explain this effect, but suggests an adaptive response to the exercise stimulus on the epigenetic level.

Hot and cold exposure triggers distinct transcriptional and behavioral responses in laboratory-inbred pond snails

Animals exhibit remarkable behavioral and molecular adaptations to cope with thermal stressors, which are crucial for survival in variable environments that are exacerbated by climate change. Aquatic poikilotherms like our model organism—the pond snail Lymnaea stagnalis—face significant challenges due to their dependence on external temperatures. Our study provides valuable insights into the different behavioral and molecular responses of lab-inbred snails to cold and heat shock stressors (i.e., 4 °C and 30 °C), particularly in the context of learning and memory formation. We found that while short-term (1 h) cold exposure transiently upregulated the expression levels of HSP70 and HSP40 in the snail’s central ring ganglia, prolonged cold exposure (24 h) resulted in a significant downregulation of LymMIPII and an upregulation of LymMIPR. These data suggest, albeit at the transcriptional level, the existence of a negative feedback loop necessary for sustaining cellular functions when metabolic demands might shift towards conserving energy during prolonged cold exposure. At the behavioral level, we found that, compared to heat shock, cold exposure did not result in a Garcia effect (i.e., a “special form” of conditioned taste aversion). The difference in memory outcomes was associated with changes in the expression levels of selected targets involved in neuronal plasticity and the stress response. While both cold and heat shock upregulated the HSP levels in the snail's central ring ganglia, cold exposure did not affect the expression levels of the neuroplasticity genes LymGRIN1 and LymCREB1, contrasting with heat shock’s neurogenic effects. Overall, this study provides insights into L. stagnalis's adaptive responses to thermal stressors, emphasizing different molecular strategies for coping with heat versus cold challenges in aquatic environments. These findings contribute to our understanding of thermal biology and stress physiology in aquatic organisms, underscoring the importance of molecular mechanisms in shaping species' resilience in dynamic environments.

Halocins and C50 Carotenoids from Haloarchaea: Potential Natural Tools against Cancer.

Haloarchaea are a group of moderate and extreme halophilic microorganisms, belonging to the Archaea domain, that constitute relevant microbial communities in salty environments like coastal and inland salted ponds, marshes, salty lagoons, etc. They can survive in stress conditions such as high salinity and, therefore, high ionic strength, high doses of ultraviolet radiation (UV), high temperature, and extreme pH values. Consequently, most of the species can be considered polyextremophiles owing to their ability to respond to the multiple extreme conditions characterizing their natural habitats. They cope with those stresses thanks to several molecular and metabolic adaptations. Thus, some of the molecules produced by haloarchaea show significantly different biological activities and physicochemical properties compared to their bacterial counterparts. Recent studies have revealed promising applications in biotechnology and medicine for these biomolecules. Among haloarchaeal biomolecules, rare natural pigments (C50 carotenoids) and small peptides called halocins and microhalocins have attracted attention worldwide due to their effects on animal and human commercial tumoral cells, apart from the role as antibiotics described for halocins or the immunomodulatory activity reported from C50 carotenoids like bacterioruberin. This review summarizes recent knowledge on these two types of biomolecules in connection with cancer to shed new light on the design of drugs and new therapies based on natural compounds.

Brain gene expression reveals pathways underlying nocturnal migratory restlessness

Migration is one of the most extreme and energy demanding life history strategies to have evolved in the animal kingdom. In birds, champions of long-distance migrations, the seasonal emergence of the migratory phenotype is characterised by rapid physiological and metabolic remodelling, including substantial accumulation of fat stores and increases in nocturnality. The molecular underpinnings and brain adaptations to seasonal migrations remain poorly understood. Here, we exposed Common quails (Coturnix coturnix) to controlled changes in day length to simulate southward autumn migration, and then blocked the photoperiod until birds entered the non-migratory wintering phase. We first performed de novo RNA-Sequencing from selected brain samples (hypothalamus) collected from birds at a standardised time at night, either in a migratory state (when restlessness was highest and at their body mass peak), or in a non-migratory state and conducted differential gene expression and functional pathways analyses. We found that the migratory state was associated with up-regulation of a few, yet functionally well defined, gene expression networks implicated in fat trafficking, protein and carbohydrate metabolism. Further analyses that focused on candidate genes (apolipoprotein H or APOH, lysosomal associated membrane protein-2 or LAMP2) from samples collected during the day or night across the entire study population suggested differences in the expression of these genes depending on the time of the day with the largest expression levels being found in the migratory birds sampled at night. We also found that expression of APOH was positively associated with levels of nocturnal activity in the migratory birds; such an association was absent within the non-migratory birds. Our results provide novel experimental evidence revealing that hypothalamic changes in expression of apolipoprotein pathways, which regulate the circulatory transport of lipids, are likely key regulatory activators of nocturnal migratory movements. Our study paves the way for performing deeper functional investigations on seasonal molecular remodelling underlying the development of the migratory phenotype.

Plasma adenosine deaminase-1 and -2 activities are lower at birth in Papua New Guinea than in The Gambia but converge over the first weeks of life.

Dynamic cellular and molecular adaptations in early life significantly impact health and disease. Upon birth, newborns are immediately challenged by their environment, placing urgent demands on the infant immune system. Adenosine deaminases (ADAs) are enzymatic immune modulators present in two isoforms - ADA-1 and ADA-2. Infants exhibit low ADA activity, resulting in high plasma adenosine concentrations and a consequent anti-inflammatory/anti-Th1 bias. While longitudinal studies of plasma ADA have been conducted in infants in The Gambia (GAM), little is known regarding ADA trajectories in other parts of the world. Herein, we characterized plasma ADA activity in an infant cohort in Papua New Guinea (PNG; n=83) and compared to ontogeny of ADA activity in a larger cohort in GAM (n=646). Heparinized peripheral blood samples were collected at day of life (DOL) 0, DOL7, DOL30, and DOL128. Plasma ADA-1, ADA-2, and total ADA activities were measured by chromogenic assay. Compared to GAM infants, PNG infants had significantly lower ADA-1 (0.9-fold), ADA-2 (0.42-fold), and total ADA (0.84-fold) activities at birth which converged by DOL30. Overall, discovery of a distinct baseline and a consistent pattern of increasing plasma ADA activity in early life in two genetically and geographically distinct populations validates and extends previous findings on the robustness of early life immune ontogeny.

Synergy of exercise and hypoxia for brain health and aging – A narrative review

Regular exercise is a well-established means to improve brain health and prevent age-related neurological diseases, including dementia (Marques-Aleixo et al., 2020). The precise mechanisms how direct exercise effects are transmitted to the brain remain incompletely understood. However, the increased oxygen demand and associated metabolic stress in the primarily affected tissues – the working skeletal muscle, the cardiovascular and the respiratory system – likely play crucial roles in exercise-signalling to the brain (Severinsen & Pedersen, 2020). Besides the mobilization of beneficial circulating factors, the modulation of blood properties and blood-flow, the immune system and the autonomous system are involved. Intriguingly, physiological stress induced by low environmental oxygen availability (hypoxia) can induce the activation of similar processes like exercise. The aim of this contribution is to evaluate the role of hypoxia in the benefits of exercise on the brain. Accumulating evidence demonstrates the potential of direct modulation of inspired oxygen levels to improve neurological diseases (Burtscher et al., 2021). Reduced all-cause mortality in people living at moderate altitudes (and therefore in chronic, mild hypobaric hypoxia) may also be associated with reduced risk of neurological diseases, including of stroke (Faeh et al., 2009). This is surprising, because the hypoxic stress at moderate altitudes (usually defined as altitudes between 1,500 and 2,500 m) is generally considered too low to induce substantial hypoxia adaptations. It is thus possible that the combination of moderate environmental hypoxia at moderate altitude with the increased oxygen demand during exercise is required to promote protective adaptations, such as of the brain. Considering this possibility, synergistic and complementary molecular and systemic responses and adaptations to exercise and hypoxia may benefit the brain. Among the involved molecular processes are mitochondrial changes following cellular stress that are also linked to the regulation of adaptations by the transcription factor hypoxia inducible factor, which is activated by both hypoxia and exercise. Mitochondria are the main molecular oxygen consumers, respond sensitively to stress and dispose of a wide array of intra- and intercellular communication modes (Memme et al., 2021). Moreover, exerkines, blood-borne factors released in response to exercise, have emerged as important mediators of inter-organ exercise-signalling (Severinsen & Pedersen, 2020) and modulate the autonomic and immune system in response to hypoxic and metabolic stress. In conclusion, the activation of endogenous responses to hypoxic and metabolic stress are powerful means to improve brain health and healthy aging. Based on the overlapping and distinct physiological responses to hypoxia and exercise, brain benefits of exercising at higher altitudes and advances in the development of customized strategies to improve brain resilience are promising approaches to target neurological diseases. While the safe performance of exercise in moderate altitudes is already considered an impactful way to improve brain health, the optimization of combined exercise and (artificially induced) hypoxia for specific target groups requires further in-depth investigation. References Burtscher, J., Mallet, R. T., Burtscher, M., & Millet, G. P. (2021). Hypoxia and brain aging: Neurodegeneration or neuroprotection? Ageing Research Reviews, 68, Article 101343. https://doi.org/10.1016/j.arr.2021.101343 Faeh, D., Gutzwiller, F., Bopp, M., & Group, S. N. C. S. (2009). Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland. Circulation, 120(6), 495-501. https://doi.org/10.1161/CIRCULATIONAHA.108.819250 Marques-Aleixo, I., Beleza, J., Sampaio, A., Stevanović, J., Coxito, P., Gonçalves, I., Ascensão, A., & Magalhães, J. (2020). Preventive and therapeutic potential of physical exercise in neurodegenerative diseases. Antioxidants & Redox Signaling, 34(8), 674–693. https://doi.org/10.1089/ars.2020.8075 Memme, J. M., Erlich, A. T., Phukan, G., & Hood, D. A. (2021). Exercise and mitochondrial health. The Journal of Physiology, 599(3), 803-817. https://doi.org/10.1113/jp278853 Severinsen, M. C. K., & Pedersen, B. K. (2020). Muscle-organ crosstalk: The emerging roles of myokines. Endocrine Reviews, 41(4), 594-609. https://doi.org/10.1210/endrev/bnaa016

The transcriptional integration of environmental cues with root cell type development.

Plant roots navigate the soil ecosystem with each cell type uniquely responding to environmental stimuli. Below ground, the plant's response to its surroundings is orchestrated at the cellular level, including morphological and molecular adaptations that shape root system architecture as well as tissue and organ functionality. Our understanding of the transcriptional responses at cell type resolution has been profoundly enhanced by studies of the model plant Arabidopsis thaliana. However, both a comprehensive view of the transcriptional basis of these cellular responses to single and combinatorial environmental cues in diverse plant species remains elusive. In this review, we highlight the ability of root cell types to undergo specific anatomical or morphological changes in response to abiotic and biotic stresses or cues and how they collectively contribute to the plant's overall physiology. We further explore interconnections between stress and the temporal nature of developmental pathways and discuss examples of how this transcriptional reprogramming influences cell type identity and function. Finally, we highlight the power of single-cell and spatial transcriptomic approaches to refine our understanding of how environmental factors fine tune root spatiotemporal development. These complex root system responses underscore the importance of spatiotemporal transcriptional mapping, with significant implications for enhanced agricultural resilience.

Unravelling stress granules in the deep cold: Characterisation of TIA-1 gene sequence in Antarctic fish species

Stress granules (SGs) are cytoplasmic foci lacking membranes, comprising non-translating messenger ribonucleoproteins, translational initiation factors, and additional proteins. Their formation is crucial for rapidly modulating gene expression in response to adverse environmental conditions, such as pollution and infections. Limited research has focused on investigating the molecular components of SGs in fish, with minimal exploration in Antarctic fish. This study characterises for the first time the transcript sequences of one key protein component of SGs, TIA-1 (T-cell intracellular antigen 1), in two Antarctic endemic fish species, i.e. Trematomus bernacchii and Chionodraco hamatus. The mRNA-binding protein TIA-1 acts as a post-transcriptional regulator of gene expression and its aggregation leads to the formation of SGs in response to cellular damage. The in vitro and bioinformatic analyses of the TIA-1 gene sequences of these two species highlighted interesting peculiarities, which include the transcription of alternatively spliced isoforms unique to the notothenioid lineage, potentially unlocking further insights into their unique adaptations to extreme environmental conditions. This is the first study to analyze tia-1 expression levels in different tissues of Antarctic fish species. Our key findings indicate that the TIA-1 gene is expressed at particularly high levels in the liver and spleen of C. hamatus, as well as in the heart and skeletal muscle of T. bernacchii. This suggests that those tissues play a significant role in the stress response mechanisms of the studied species. This study provides novel insights into the molecular adaptations of Antarctic fish, highlighting the potential importance of TIA-1 in their response to environmental stressors. The unique features of TIA-1 identified in these species may offer broader implications for understanding how Antarctic fish regulate gene transcriptions in their extreme environments.

Abstract B004: Targeting Metabolic Vulnerabilities in Pancreatic Cancer: The Synergistic Anti- Tumor Effects of a Ketogenic Diet and IDH1 Inhibition

Abstract Background: A ketogenic diet, characterized by high fat (90% kCal) and low carbohydrates (5% kCal), induces ketosis. Previous research suggests that a ketogenic diet shifts cancer cell metabolism from glycolysis to the tricarboxylic acid (TCA) cycle in the mitochondria. While the overall impact on cancer growth remains uncertain, most studies suggest an anti-cancer effect. We hypothesize that understanding the molecular and biochemical adaptations of pancreatic cancer cells to a ketogenic diet will reveal metabolic vulnerabilities and lead to rational therapeutic strategies that complement the diet. Methods: Mice were fed a ketogenic diet, with control mice on a normal diet. Pancreatic cancer xenografts were monitored for growth and subjected to biochemical analyses. Tumor metabolites were measured using LC/GC-MS, and oxidative stress was assessed by NADP+/NADPH, NAD+/NADH levels, and lipid peroxidation assays. Enzyme expression was determined by Western blot. In vitro, mitochondrial function was analyzed using the Seahorse FX Analyzer, and cell growth was measured by PicoGreen DNA quantitation. Results: A ketogenic diet slowed pancreatic cancer growth in multiple in vivo models, including MIA-PaCa2, KPC, and patient-derived xenografts. TCA metabolites increased in xenografts exposed to the ketogenic diet, with a significant upregulation of TCA cycle-associated enzymes. Specifically, the expression of BDH1 (a ketolytic enzyme), IDH1 (supports antioxidant defense and mitochondrial function), and IDH2 (mitochondrial homolog of IDH1) were elevated. Conversely, the glycolytic enzyme G3P was reduced. Additionally, a ketogenic diet induced oxidative stress in pancreatic cancer in vivo. Combining a ketogenic diet with an IDH1 inhibitor impaired antioxidant defense and mitochondrial function, resulting in significantly reduced tumor proliferation compared to either treatment alone. In vitro studies indicated that low glucose and fatty acids primarily drive the reduced proliferation of pancreatic cancer cells on a ketogenic diet, while exogenous ketone bodies are utilized for energy under glucose deprivation, generally promoting tumor growth. Conclusion: A ketogenic diet exerts a strong anti-tumor effect in multiple pancreatic cancer mouse models, likely due to low glucose and increased fatty acid load. The metabolic shift towards an oxidative phosphorylation (OXPHOS) phenotype makes pancreatic cancer cells particularly vulnerable to antioxidant and mitochondrial inhibitors. Citation Format: Omid Hajihassani, Mehrdad Zarei, Soubhi Tahan, Peter Gallagher, William Beegan, John Speers, James Choi, Aya Murray, Alexander Loftus, Helen Cheng, Anusha Mudigonda, Karen Ji, Jonathan Hue, Hallie Graor, Jordan Winter. Targeting Metabolic Vulnerabilities in Pancreatic Cancer: The Synergistic Anti- Tumor Effects of a Ketogenic Diet and IDH1 Inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B004.