Heterocephalus Research Articles

CD44 correlates with longevity and enhances basal ATF6 activity and ER stress resistance

The naked mole rat (NMR) is the longest-lived rodent, resistant to multiple age-related diseases including neurodegeneration. However, the mechanisms underlying the NMR's resistance to neurodegenerative diseases remain elusive. Here, we isolated oligodendrocyte progenitor cells (OPCs) from NMRs and compared their transcriptome with that of other mammals. Extracellular matrix (ECM) genes best distinguish OPCs of long- and short-lived species. Notably, expression levels of CD44, an ECM-binding protein that has been suggested to contribute to NMR longevity by mediating the effect of hyaluronan (HA), are not only high in OPCs of long-lived species but also positively correlate with longevity in multiple cell types/tissues. We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA. HA-independent role of CD44 in proteostasis regulation may contribute to mammalian longevity.

Phylogenetic modeling of enhancer shifts in African mole-rats reveals regulatory changes associated with tissue-specific traits.

Changes in gene regulation are thought to underlie most phenotypic differences between species. For subterranean rodents such as the naked mole-rat, proposed phenotypic adaptations include hypoxia tolerance, metabolic changes, and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the naked mole-rat, the mole-rat clade, or are also present in other mammals. Here, we investigate regulatory evolution in the heart and liver from two African mole-rat species and two rodent outgroups using genome-wide epigenomic profiling. First, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous regulatory elements and identified thousands of promoter and enhancer regions with differential epigenomic activity in mole-rats. These elements associate with known mole-rat adaptations in metabolic and functional pathways and suggest candidate genetic loci that may underlie mole-rat innovations. Second, we evaluated ancestral and species-specific regulatory changes in the study phylogeny and report several candidate pathways experiencing stepwise remodeling during the evolution of mole-rats, such as the insulin and hypoxia response pathways. Third, we report nonorthologous regulatory elements overlap with lineage-specific repetitive elements and appear to modify metabolic pathways by rewiring of HNF4 and RAR/RXR transcription factor binding sites in mole-rats. These comparative analyses reveal how mole-rat regulatory evolution informs previously reported phenotypic adaptations. Moreover, the phylogenetic modeling framework we propose here improves upon the state of the art by addressing known limitations of inter-species comparisons of epigenomic profiles and has broad implications in the field of comparative functional genomics.

Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice.

Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent-the naked mole-rat1,2. To study whether the benefits of HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.

LB1794 Mechanisms regulating scar-free wound healing in long-lived naked mole-rats

LB1794 Mechanisms regulating scar-free wound healing in long-lived naked mole-rats

End fire linear antenna array synthesis using differential evolution inspired Adaptive Naked Mole Rat Algorithm

Linear antenna arrays (LAAs) play a critical role in smart system communication applications such as the Internet of Things (IoT), mobile communication and beamforming. However, minimizing secondary lobes while maintaining a low beamwidth remains challenging. This study presents an enhanced synthesis methodology for LAAs using the Adaptive Naked Mole Rat Algorithm (ANMRA). ANMRA, inspired by mole-rat mating habits, improves exploration and exploitation capabilities for directive LAA applications. The performance of ANMRA is assessed using the CEC 2019 benchmark test functions, a widely adopted standard for statistical evaluation in optimization algorithms. The proposed methodology results are also benchmarked against state-of-the-art algorithms, including the Salp Swarm Algorithm (SSA), Cuckoo Search (CS), Artificial Hummingbird Algorithm (AHOA), Chimp Optimization Algorithm (ChOA), and Naked Mole Rat Algorithm (NMRA). The results demonstrate that ANMRA achieves superior performance among the benchmarked algorithms by successfully minimizing secondary lobes and obtaining a narrow beamwidth. The ANMRA controlled design achieves the lowest Side Lobe Level (SLL) of − 37.08 dB and the smallest beamwidth of 74.68°. The statistical assessment using the benchmark test functions further confirms the effectiveness of ANMRA. By optimizing antenna element magnitude and placement control, ANMRA enables precise primary lobe placement, grating lobe elimination, and high directivity in LAAs. This research contributes to advancing smart system communication technologies, particularly in the context of IoT and beamforming applications, by providing an enhanced synthesis methodology for LAAs that offers improved performance in terms of secondary lobe reduction and beamwidth optimization.

The Evolution and Ecology of Oxidative and Antioxidant Status: A Comparative Approach in African Mole-Rats.

The naked mole-rat of the family Bathyergidae has been the showpiece for ageing research as they contradict the traditional understanding of the oxidative stress theory of ageing. Some other bathyergids also possess increased lifespans, but there has been a remarkable lack of comparison between species within the family Bathyergidae. This study set out to investigate how plasma oxidative markers (total oxidant status (TOS), total antioxidant capacity (TAC), and the oxidative stress index (OSI)) differ between five species and three subspecies of bathyergids, differing in their maximum lifespan potential (MLSP), resting metabolic rate, aridity index (AI), and sociality. We also investigated how oxidative markers may differ between captive and wild-caught mole-rats. Our results reveal that increased TOS, TAC, and OSI are associated with increased MLSP. This pattern is more prevalent in the social-living species than the solitary-living species. We also found that oxidative variables decreased with an increasing AI and that wild-caught individuals typically have higher antioxidants. We speculate that the correlation between higher oxidative markers and MLSP is due to the hypoxia-tolerance of the mole-rats investigated. Hormesis (the biphasic response to oxidative stress promoting protection) is a likely mechanism behind the increased oxidative markers observed and promotes longevity in some members of the Bathyergidae family.

Cellular senescence induction leads to progressive cell death via the INK4a-RB pathway in nakedmole-rats.

Naked mole-rats (NMRs) have exceptional longevity and are resistant to age-related physiological decline and diseases. Given the role of cellular senescence in aging, we postulated that NMRs possess unidentified species-specific mechanisms to prevent senescent cell accumulation. Here, we show that upon induction of cellular senescence, NMR fibroblasts underwent delayed and progressive cell death that required activation of the INK4a-retinoblastoma protein (RB) pathway (termed "INK4a-RB cell death"), a phenomenon not observed in mouse fibroblasts. Naked mole-rat fibroblasts uniquely accumulated serotonin and were inherently vulnerable to hydrogen peroxide (H2 O2 ). After activation of the INK4a-RB pathway, NMR fibroblasts increased monoamine oxidase levels, leading to serotonin oxidization and H2 O2 production, which resulted in increased intracellular oxidative damage and cell death activation. In the NMR lung, induction of cellular senescence caused delayed, progressive cell death mediated by monoamine oxidase activation, thereby preventing senescent cell accumulation, consistent with in vitro results. The present findings indicate that INK4a-RB cell death likely functions as a natural senolytic mechanism in NMRs, providing an evolutionary rationale for senescent cell removal as a strategy to resist aging.

Chromosome-level Asian elephant genome assembly and comparative genomics of long-lived mammals reveal the common substitutions for cancer resistance.

The naked mole rat (Heterocephalus glaber), bats (e.g., genus Myotis), and elephants (family Elephantidae) are known as long-lived mammals and are assumed to be excellent cancer antagonists. However, whether there are common genetic changes underpinning cancer resistance in these long-lived species is yet to be fully established. Here, we newly generated a high-quality chromosome-level Asian elephant (Elephas maximus) genome and identified that the expanded gene families in elephants are involved in Ras-associated and base excision repair pathways. Moreover, we performed comparative genomic analyses of 12 mammals and examined genes with signatures of positive selection in elephants, naked mole rat, and greater horseshoe bat. Residues at positively selected sites of CDR2L and ALDH6A1 in these long-lived mammals enhanced the inhibition of tumor cell migration compared to those in short-lived relatives. Overall, our study provides a new genome resource and a preliminary survey of common genetic changes in long-lived mammals.

Enhancing predictions of blast-induced ground vibration in open-pit mines: Comparing swarm-based optimization algorithms to optimize self-organizing neural networks

The objective of this paper is to present a method for predicting blast-induced ground vibration in open-pit mines that is based on the use of self-organizing neural networks (SONIA) and metaheuristic algorithms. In order to improve the accuracy of the SONIA model, several metaheuristic algorithms were employed, including the Manta Ray Foraging Optimization (MRFO), Hunger Games Search (HGS), Aquila Optimization (AO), and Naked Mole-Rat Algorithm (NMRA). Additionally, the k-fold cross-validation technique was used to identify the best parameters for the algorithms, which were then used to retrain the models for predicting blast-induced ground vibration. The effectiveness of the proposed method was evaluated using a case study of an open-pit coal mine in Vietnam, which had 288 blasting events. The study found that SONIA was a suitable neural network for predicting blast-induced ground vibration due to its self-organizing structure, even with a small dataset containing complex relationships. However, the SONIA model could be further optimized using the metaheuristic algorithms to improve its accuracy. The study found that the MRFO-SONIA model was the most reliable and accurate, with the lowest error (MAE = 0.379, RMSE = 0.453, MAPE = 0.08) and the highest reliability (R2 = 0.896). Meanwhile, the HGS-SONIA, AO-SONIA, and NMRA-SONIA models provided lower performance, with MAE values of 0.455, 0.500, and 0.492, RMSE values of 0.552, 0.603, and 0.580, MAPE values of 0.100, 0.112, and 0.111, and R2 values of 0.845, 0.815, and 0.829, respectively. The results of this study demonstrated the potential of using metaheuristic-based SONIA models to enhance predictions of blast-induced ground vibration in open-pit mines. This approach could prove useful in other operations in open-pit mines where there is a need to predict vibrations or other disturbances/negative effects resulting from specific mining activities.

Hybrid binary grey wolf naked mole-rat algorithm for fragment-type UWB antenna optimization using time-varying transfer functions

This paper introduces a novel hybrid binary variant of the Grey Wolf Optimizer (GWO) and the Naked Mole-Rat Algorithm (NMRA), called HbGNMR. The primary objective of this hybridization is to overcome the poor exploration and local optima stagnation problems of the basic NMRA as well as the poor exploitation of GWO. HbGNMR incorporates the global search strategy of GWO into the worker phase to enhance exploration, and a mating factor based on simulated annealing-inertia weight is added to the breeder phase to improve exploitation. Moreover, fourteen new time-varying binary transfer functions of two families: seven S-shaped and seven V-shaped functions have been analysed. Among these transfer functions, TVV5 was identified as the most effective in converting solutions from continuous search space to binary search space and maintaining a balance between exploration and exploitation phases. The hybrid performance of HbGNMR is evaluated on twenty-three CEC’05, thirty CEC’17, and eighty CEC’21 benchmark functions. The statistical results demonstrate that HbGNMR outperforms nine well-known state-of-the-art algorithms according to Friedman-test and Wilcoxon rank-sum test. To test the effectiveness of the proposed algorithm for real-world applications, HbGNMR is employed to optimize a large dimensional planar-monopole ultrawideband (UWB) fragment-type antenna structure of an 18 × 18 binary matrix cells. Experimental testing of the prototype is conducted on a vector-network-analyser-based experimental-testbed, which shows good agreement with the simulated results. Furthermore, the optimized structure achieves large bandwidth (3.1-12.6 GHz), excellent gain, and high directivity for the 10 × 15 mm2 compact size UWB antenna geometry. Therefore, the optimized antenna can be utilized for modern wireless applications.

Investigation of Clock Gene Variations in Nannospalax Cytotypes

Blind mole rats (Nannospalax) are subterranean mammals noted for their longevity and cancerresistance. It is known that these animals' vestigial eyes, particularly the Harder gland around the eyes, maygenerate considerable amounts of melatonin. Furthermore, the melatonin production mechanism in thecircadian rhythm cycle of blind mole rats is regarded to be different from that of other living beings. Themelatonin and Clock genes are hypothesized to be linked to the formation, development, and spread ofcancer, but the researchers still cannot explain their extraordinary cancer resistance.In this study, we hypothesized that the melatonin production mechanism in the circadian rhythm cycle ofblind mole rats, which have been shown in the literature to be cancer-resistant, may differ from that of otherliving species due to the difference in their amino acid variations. Differences in the DNA of the Clockgenes (Cry1 and Per1) involved in melatonin biosynthesis in blind mole rats were studied compared toother model species (Spalax galili, Mus musculus, Heterocephalus glaber, Rattus norvegicus, and Homosapiens). As a result, while no variations were found in the Cry1 gene; only p.G7R variation was found inthe Per1 gene. The SNAP2 software had demonstrated that the human analogs of this variation harmfuleffects. It was suggested that more or full exon sites, more samples and genes should be studied to observemore variants in Nannospalax species. Thereby, the cancer resistance of blind mole rats may be explainedbetter by these variations and the functions of protein domains where these variants are located in.

Comparative analysis of bats and rodents’ genomes suggests a relation between non-LTR retrotransposons, cancer incidence, and ageing

The presence in nature of species showing drastic differences in lifespan and cancer incidence has recently increased the interest of the scientific community. In particular, the adaptations and the genomic features underlying the evolution of cancer-resistant and long-lived organisms have recently focused on transposable elements (TEs). In this study, we compared the content and dynamics of TE activity in the genomes of four rodent and six bat species exhibiting different lifespans and cancer susceptibility. Mouse, rat, and guinea pig genomes (short-lived and cancer-prone organisms) were compared with that of naked mole rat (Heterocephalus glaber) which is a cancer-resistant organism and the rodent with the longest lifespan. The long-lived bats of the genera Myotis, Rhinolophus, Pteropus and Rousettus were instead compared with Molossus molossus, which is one of the organisms with the shortest lifespan among the order Chiroptera. Despite previous hypotheses stating a substantial tolerance of TEs in bats, we found that long-lived bats and the naked mole rat share a marked decrease of non-LTR retrotransposons (LINEs and SINEs) accumulation in recent evolutionary times.

LS-DN Algorithm Based User Matching and Power Minimization in NOMA Disaster Communication

<p>To address the limited and time delay disaster communication, a joint optimization scheme integrates the advantages of differential evolution algorithm (DE) and naked mole- rat algorithm (NMR), and proposes Lévy and sigmoidal DE-NMR, namely LS-DN. LS-DN applies the Lévy flight parameters of adaptive features and sigmoidal selection factor (λ) to the worker of NMR phase, and optimizes the crossover rate (CR) and variation parameter (F) in the DE algorithm, to obtain a balance the exploration and development capabilities. The proposed LS-DN algorithm is used to optimize the user aggregation scheme, since an effect aggregation of disaster victims can reduce power consumption and improve system performance. An value of power external function (Cfn ) is defined for each disaster victim, which is expressed as the system power consumption value for each disaster victim under different aggregation schemes. To minimize the microcell power without deteriorating the quality of service (QoS), it is demonstrated by analyzing the relevant characteristics of non-orthogonal multiple access（NOMA）disaster communication that the power consumption strongly depends on user aggregation method and power allocation. The significance of joint optimization for improving the performance of NOMA disaster communication systems is also emphasized. Simulation results show that LS-DN is able to significantly reduce the power consumption of the system. With the application of LS-DN, the throughput of NOMA system increases by 65% compared to the conventional orthogonal multiple access (OMA) system.</p> <p> </p>

Naked Mole-Rat Cortex Maintains Reactive Oxygen Species Homeostasis During In Vitro Hypoxia or Ischemia and Reperfusion.

Neuronal injury during acute hypoxia, ischemia, and following reperfusion are partially attributable to oxidative damage caused by deleterious fluctuations of reactive oxygen species (ROS). In particular, mitochondrial superoxide (O2•-) production is believed to upsurge during lowoxygen conditions and also following reperfusion, before being dismutated to H2O2 and released into the cell. However, disruptions of redox homeostasis may be beneficially attenuated in the brain of hypoxia-tolerant species, such as the naked mole-rat (NMR, Heterocephalus glaber). As such, we hypothesized that ROS homeostasis is better maintained in the brain of NMRs during severe hypoxic/ ischemic insults and following reperfusion. We predicted that NMR brain would not exhibit substantial fluctuations in ROS during hypoxia or reoxygenation, unlike previous reports from hypoxiaintolerant mouse brain. To test this hypothesis, we measured cortical ROS flux using corrected total cell fluorescence measurements from live brain slices loaded with the MitoSOX red superoxide (O2•-) indicator or chloromethyl 2',7'-dichlorodihydrofluorescein diacetate (CM-H2-DCFDA; which fluoresces with whole-cell hydrogen peroxide (H2O2) production) during various low-oxygen treatments, exogenous oxidative stress, and reperfusion. We found that NMR cortex maintained ROS homeostasis during low-oxygen conditions, while mouse cortex exhibited a ~40% increase and a ~30% decrease in mitochondrial O2•- and cellular H2O2 production, respectively. Mitochondrial ROS homeostasis in NMRs was only disrupted following sodium cyanide application, which was similarly observed in mice. Our results suggest that NMRs have evolved strategies to maintain ROS homeostasis during acute bouts of hypoxia and reoxygenation, potentially as an adaptation to life in an intermittently hypoxic environment.

Damaraland mole-rats do not rely on helpers for reproduction or survival.

In eusocial invertebrates and obligate cooperative breeders, successful reproduction is dependent on assistance from non-breeding group members. Although naked (Heterocephalus glaber) and Damaraland mole-rats (Fukomys damarensis) are often described as eusocial and their groups are suggested to resemble those of eusocial insects more closely than groups of any other vertebrate, the extent to which breeding individuals benefit from the assistance of non-breeding group members is unclear. Here we show that, in wild Damaraland mole-rats, prospective female breeders usually disperse and settle alone in new burrow systems where they show high survival rates and remain in good body condition-often for several years-before being joined by males. In contrast to many obligate cooperative vertebrates, pairs reproduced successfully without non-breeding helpers, and the breeding success of experimentally formed pairs was similar to that of larger, established groups. Though larger breeding groups recruited slightly more pups than smaller groups, adult survival was independent of group size and group size had mixed effects on the growth of non-breeders. Our results suggest that Damaraland mole-rats do not need groups to survive and that cooperative breeding in the species is not obligate as pairs can-and frequently do-reproduce without the assistance of helpers. While re-emphasizing the importance of ecological constraints on dispersal in social mole-rats, the mixed effects of group size in our study suggest that indirect benefits accrued through cooperative behavior may have played a less prominent role in the evolution of mole-rat group-living than previously thought.

Translational application of adaptive physiology in non-traditional animal models

Many mammals have naturally evolved solutions to human biomedical problems. The genes and regulatory elements underlying their protective strategies are generally neither novel nor species-specific, but rather shared among all mammals, including humans. Adaptive physiology published in the literature provides a starting point to identify species with natural disease resistance in which to identify genomic targets that can be translated to therapeutics. When searching through available datasets for species of interest and evaluating the quality of existing transcriptomic, proteomic and genomic analyses, we prioritize species that would best integrate into our drug target discovery platform “Convergence.” Convergence consists of five unique applications to identify and validate the genomic loci underlying these phenomena synthesizing multi-omics data from mammals capable of resisting and reversing human pathologies and present a promising avenue towards development of new treatments. Here we present this target discovery platform, demonstrate examples from current bio-banked species, and explore the potential of using a phylogenetic approach for novel target discovery for the betterment of human health. Our foundational data included transcriptomic and epigenomic sequencing from bio-banked 13-lined ground squirrel (13-LGS) tissues collected at precise physiological time-points across hibernation. Convergence also incorporates multi-omic data sets curated from the literature for many disease-resistant species, as well as human data from hundreds of thousands of individuals. As an example application, the 13-LGS experiences multiple hypometabolic challenges during hibernation, including conditions of ischemic stress and reperfusion, yet these animals resist tissue pathology that would be expected in humans experiencing these conditions. Using bulk RNA-seq data, we applied Weighted Gene Correlation Network Analysis (WGCNA) and Corenet, two network-focused approaches, to identify coexpression networks and hub genes associated with physiological states of hibernation. Many of the identified gene coexpression modules were enriched for genes linked to hibernation physiology-relevant diseases including steatohepatitis and myocardial ischemia via DisGeNet. These enrichments suggest that genes driving hibernation states in the 13-LGS may also hold the key to human-relevant disease resistance and reversal. After our success with the 13-LGS model, we are focused on extending our methodology to other species. Naked mole rats have a resistance to cancer, the northern elephant seal is resistant to diabetes and obesity, and jellyfish exhibit regenerative potential that may be applied to neurons in humans. By applying Fauna’s Convergence platform to questions around disease resistance and reversal paradigms in multiple species, we are developing human therapeutics for a variety of clinical indications using solutions derived from evolutionary problem-solving. The authors are employed by Fauna Bio Inc. and invested in their commercial success. This is the full abstract presented at the American Physiology Summit 2023 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.

Validation of Enzyme Immunoassays via an Adrenocorticotrophic Stimulation Test for the Non-Invasive Quantification of Stress-Related Hormone Metabolites in Naked Mole-Rats.

Small size in mammals usually restricts long-term, frequent monitoring of endocrine function using plasma as a matrix. Thus, the non-invasive monitoring of hormone metabolite concentrations in excreta may provide an invaluable approach. The aim of the current study was to examine the suitability of enzyme immunoassays (EIAs) for monitoring responses to stressors in the naked mole-rat (Heterocephalus glaber, NMR) using urine and feces as hormone matrices. A saline control administration, and a high- and low-dose adrenocorticotropic hormone (ACTH) challenge were performed on six male and six female disperser morph NMRs. The results revealed that a 5α-pregnane-3β,11β,21-triol-20-one EIA detecting glucocorticoid metabolites (GCMs) with a 5α-3β-11β-diol structure is the most suitable assay for measuring concentrations in male urine samples, whereas an 11-oxoaetiocholanolone EIA detecting GCMs with a 5β-3α-ol-11-one structure appears the most suitable EIA for quantifying GCMs in female urine. An 11-oxoaetiocholanolone EIA detecting 11,17 dioxoandrostanes was the most suitable EIA for quantifying GCMs in the feces of both sexes. There were sex-related differences in response to the high- and low-dose ACTH challenge. We recommend using feces as a more suitable matrix for non-invasive GCM monitoring for NMRs which can be valuable when investigating housing conditions and other welfare aspects.

Macrophages from naked mole-rat possess distinct immunometabolic signatures upon polarization.

The naked mole-rat (NMR) is a unique long-lived rodent which is highly resistant to age-associated disorders and cancer. The immune system of NMR possesses a distinct cellular composition with the prevalence of myeloid cells. Thus, the detailed phenotypical and functional assessment of NMR myeloid cell compartment may uncover novel mechanisms of immunoregulation and healthy aging. In this study gene expression signatures, reactive nitrogen species and cytokine production, as well as metabolic activity of classically (M1) and alternatively (M2) activated NMR bone marrow-derived macrophages (BMDM) were examined. Polarization of NMR macrophages under pro-inflammatory conditions led to expected M1 phenotype characterized by increased pro-inflammatory gene expression, cytokine production and aerobic glycolysis, but paralleled by reduced production of nitric oxide (NO). Under systemic LPS-induced inflammatory conditions NO production also was not detected in NMR blood monocytes. Altogether, our results indicate that NMR macrophages are capable of transcriptional and metabolic reprogramming under polarizing stimuli, however, NMR M1 possesses species-specific signatures as compared to murine M1, implicating distinct adaptations in NMR immune system.

Abstract 348: Elucidation of SUMOylation machinery in human cancer cells and naked mole-rat tissues

Abstract Background: SUMOylation is a post-translational modification where small ubiquitin-like modifier (SUMO) proteins are conjugated to lysine residues of target proteins. SUMO proteins exist in all eukaryotes and participate in a catalytic cycle, which includes maturation, activation, conjugation, ligation, and de-modification. SUMOylation is known to regulate numerous molecular regulatory mechanisms such as: chromatin remodeling, DNA repair, immune responses, cell cycle progression, apoptosis, and the intracellular signal transduction. SUMOylation dysregulation is known to promote several diseases, including cancer cell survival. The unique traits of phenotypic and molecular adaptations found in naked mole rats (NMR) suggest high stability and effective functioning of the molecular machinery that counteract damage accumulation in its genome. NMR lifespan can reach up to 32 years and acquires a very efficient mechanism of resistance to cancer. This study aims to investigate the regulation of SUMO machinery between human cancer cells breast (MCF-7), colorectal (DLD-1), and neuroblastoma (SH-SY5Y)) and NMR brain and intestinal tissues, in order to find novel targets for cancer treatment. Results: The pairwise alignment identified the similarity of both SUMO genes and proteins including SUMO1, SUMO2/3, and SUMO components of Sentrin-specific protease isoforms (SENP 1-7), activation (SAE1 and Uba2), conjugation (Ubc9), and ligation isoforms (PIAS1-4) between NMR and human. In addition, qRT-PCR data revealed low expression of SUMO components at the mRNA level in NMR brain and intestinal tissues compared to MCF-7, DLD-1, and SH-SY5Y cell lines. On the contrary, PIAS4 expression is significantly higher in the NMR tissues compared to cancer cell lines. Protein analysis via Western blotting performed on MCF-7, DLD-1, and SH-SY5Y cell lines revealed similar levels to mRNA compared to NMR tissue. Ongoing studies are focusing on several functional assays to investigate effects of hUBE2I, hSENP1, and Myc/hPIAS4 effects on cytotoxicity and signaling properties of the cancer cells using techniques such as Microculture Tetrazolium (MTT), migration, invasion, and colony formation. The effect on cytotoxicity is also analyzed in relevance to clinical used treatments such as Doxorubicin in MCF-7, 5-Fluorouracil for DLD-1 and Methotrexate in SH-SY5Y. Conclusion: Expression analysis of SUMOylation machinery revealed lower expression of mRNA levels for SUMO components was observed in NMR tissues compared to all human cancer cells. However, PIAS4 expression was significantly higher in the NMR tissues compared to cancer cell lines. This data revealed important differences in NMR SUMOylation machinery (such as UBE2I, SENP1 and PIAS4) which provides a future therapeutic avenue to treat cancer. Citation Format: Mohammed Abdullah Mohammed Salih, Ritchie Williamson, Sriharsha Kantamneni. Elucidation of SUMOylation machinery in human cancer cells and naked mole-rat tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 348.

Ventilatory responses to hypoxic and hypercapnic environments in naked mole-rats.

Extreme environments are powerful drivers of physiological adaptation. Naked mole-rats offer an informative example of this relationship as they putatively encounter intermittent hypoxia and hypercapnia in their subterranean habitat. This has presumably driven the evolution of a suite of cellular and physiological adaptations that enable life in these conditions. Recently, my laboratory and others have begun to examine physiological responses to environmental hypoxia and hypercapnia in naked mole-rats, and the underlying cellular and molecular mechanisms that differentiate the responses of this species from those of other small mammals. Prominent among these adaptations are a robust hypoxic metabolic response and blunted ventilatory responses to hypoxia and hypercapnia. These responses are mediated in part by modifications to the central nervous system signaling pathways that sense and communicate changes in environmental gas levels and initiate and maintain downstream physiological responses. For example, naked mole-rats retain the signaling architecture necessary for "normal" ventilatory responses to hypoxia and hypercapnia; however, the underlying signaling pathways are muted, resulting in reduced, or even the absence of, sensitivity to otherwise powerful environmental stimuli. Herein, I discuss what we have learned about the manifestation and control of ventilatory and metabolic responses to hypoxia and hypercapnia in naked mole-rats. I also highlight areas where additional work is warranted and consider the implications of what we have learned for the ecophysiology of a species that thrives in conditions that are deleterious or lethal to most adult mammals.