Biology subjects

Suresh, S.

Publications and source records attributed to Suresh, S..

51 records · Page 3Linked to original sources

bioRxiv2023

Low-Magnitude Mechanical Signals Combined with Zoledronic Acid Reduce Musculoskeletal Weakness and Adiposity in Estrogen-Deprived Mice

Combination treatment of Low-Intensity Vibration (LIV) with zoledronic acid (ZA) was hypothesized to preserve bone mass and muscle strength while reducing adipose tissue accrual associated with complete estrogen (E2)-deprivation in young and skeletally mature mice. Complete E2-deprivation (surgical-ovariectomy (OVX) and daily injection of aromatase inhibitor (AI) letrozole) were performed on 8-week-old C57BL/6 female mice for 4 weeks following commencement of LIV administration or control (no LIV), for 28 weeks. Additionally, 16-week-old C57BL/6 female E2-deprived mice were administered {+/-}LIV twice daily and supplemented with {+/-}ZA (2.5 ng/kg/week). By week 28, lean tissue mass quantified by dual-energy X-ray absorptiometry was increased in younger OVX/AI+LIV(y) mice, with increased myofiber cross-sectional area of quadratus femorii. Grip strength was greater in OVX/AI+LIV(y) mice than OVX/AI(y) mice. Fat mass remained lower in OVX/AI+LIV(y) mice throughout the experiment compared with OVX/AI(y) mice. OVX/AI+LIV(y) mice exhibited increased glucose tolerance and reduced leptin and free fatty acids than OVX/AI(y) mice. Trabecular bone volume fraction and connectivity density increased in the vertebrae of OVX/AI+LIV(y) mice compared to OVX/AI(y) mice; however, this effect was attenuated in the older cohort of E2-deprived mice, specifically in OVX/AI+ZA mice, requiring combined LIV with ZA to increase trabecular bone volume and strength. Similar improvements in cortical bone thickness and cross-sectional area of the femoral mid-diaphysis were observed in OVX/AI+LIV+ZA mice, resulting in greater fracture resistance. Our findings demonstrate that the combination of mechanical signals in the form of LIV and anti-resorptive therapy via ZA improve vertebral trabecular bone and femoral cortical bone, increase lean mass, and reduce adiposity in mice undergoing complete E2-deprivation. One Sentence Summary: Low-magnitude mechanical signals with zoledronic acid suppressed bone and muscle loss and adiposity in mice undergoing complete estrogen deprivation. Translational RelevancePostmenopausal patients with estrogen receptor-positive breast cancer treated with aromatase inhibitors to reduce tumor progression experience deleterious effects to bone and muscle subsequently develop muscle weakness, bone fragility, and adipose tissue accrual. Bisphosphonates (i.e., zoledronic acid) prescribed to inhibit osteoclast-mediated bone resorption are effective in preventing bone loss but may not address the non-skeletal effects of muscle weakness and fat accumulation that contribute to patient morbidity. Mechanical signals, typically delivered to the musculoskeletal system during exercise/physical activity, are integral for maintaining bone and muscle health; however, patients undergoing treatments for breast cancer often experience decreased physical activity which further accelerates musculoskeletal degeneration. Low-magnitude mechanical signals, in the form of low-intensity vibrations, generate dynamic loading forces similar to those derived from skeletal muscle contractility. As an adjuvant to existing treatment strategies, low-intensity vibrations may preserve or rescue diminished bone and muscle degraded by breast cancer treatment.

cancer biology↗

bioRxiv2023

Wolbachia-infected pharaoh ant colonies have higher egg production, metabolic rate, and worker survival

Wolbachia is a widespread endosymbiotic bacteria with diverse phenotypic effects on its insect hosts. Wolbachia also commonly infects social insects, where it faces unique challenges associated with its hosts caste-based reproductive division of labor and colony living. Here we dissect the benefits and costs of Wolbachia infection on life-history traits of pharaoh ants, Monomorium pharaonis. Pharaoh ants are relatively short-lived and show natural variation in Wolbachia infection between colonies, thereby making them an ideal model system for this study. We quantified effects on the lifespan of queen and worker castes, the egg-laying rate of queens across queen lifespan, and the metabolic rates of whole colonies and colony members. Newly-infected queens laid more eggs than uninfected queens but had similar metabolic rates and lifespans. Surprisingly, infected workers outlived uninfected workers. Infected colonies were more productive due to increased queen egg-laying rates and worker longevity, and infected colonies had higher metabolic rates during peak colony productivity. While some effects of infection, such as elevated colony-level metabolic rates may be detrimental in more stressful conditions, we did not find any costs of infection under laboratory conditions. Overall, our study emphasizes the beneficial effects of Wolbachia on colony-level growth and metabolism in this species.

evolutionary biology↗

bioRxiv2022

Gobies inhabiting natural CO2 seeps reveal acclimation strategies to long-term acidification

Ocean acidification (OA) is known to affect the physiology, survival, behaviour, and fitness of various fish species with repercussions at the population, community, and ecosystem levels. Some fish species, however, seem to acclimate rapidly to OA conditions and even thrive in acidified environments. The molecular mechanisms that enable species to successfully inhabit high CO2 environments has not been fully elucidated especially in wild fish populations. Here, we used the natural CO2 seep in Vulcano Island, Italy to study the effects of elevated CO2 exposure on the brain transcriptome of the anemone goby, a species with high population density in the CO2 seep and investigate their potential for acclimation. When compared to fish from environments with ambient CO2, gobies living in the CO2 seep showed differences in expression of transcripts involved in ion transport and pH homeostasis, cellular stress, immune response, circadian rhythm, and metabolism. We also found evidence of potential adaptive mechanisms to restore the functioning of GABAergic pathways, whose activity can be affected by exposure to elevated CO2 levels. Our findings indicate that gobies living in the CO2 seep may be capable of mitigating CO2 induced oxidative stress and maintaining physiological pH while meeting the consequent increased energetic costs. The conspicuous difference in expression of core circadian rhythm transcripts could provide an adaptive advantage by increasing flexibility of physiological processes in elevated CO2 conditions thereby facilitating acclimation. Our results show potential molecular processes of acclimation to elevated CO2 in gobies enabling them to thrive in the acidified waters of Vulcano Island.

evolutionary biology↗

bioRxiv2022

Epigenetic reprogramming of melanoma cell state through fatty acid β-oxidation and Toll like receptor 4 signaling

Tumor cells respond to a host of factors from the local microenvironment. Microenvironmental fatty acids can be used by melanoma cells for fuel, but their effects on transcription and epigenetics are still unclear. Here, we show that the fatty acid {beta}-oxidation (FAO) pathway integrates signaling and epigenetics to drive melanoma progression. Using transgenic zebrafish and human cell lines, we find that octanoate, a medium-chain fatty acid, increases tumorigenesis. Octanoate is metabolized via the FAO/ACLY axis into acetyl-CoA, leading to increased histone acetylation. Transcriptomic and epigenetic analyses demonstrate a convergence of inflammatory gene signatures in octanoate-treated melanoma cells. This signature is mediated by TLR4/MyD88 signaling, which is activated by saturated fatty acids like octanoate. Genetic inactivation of either FAO enzymes or TLR4/MyD88 inhibits alterations in histone acetylation, and rescues octanoate-tumor promoting effects. Together, these data demonstrate clear evidence linking fatty acid metabolism and epigenetics to melanoma pathogenesis through TLR4 signaling.

cancer biology↗

bioRxiv2022

Long non-coding RNA as environmental regulator in a non-model fish

The majority of the transcribed genome does not have coding potential but is composed of non-coding transcripts that are involved in transcriptional and post-transcriptional regulation of protein-coding genes. Regulation of gene expression is important in determining the response of organisms to changes in the environment, and therefore their persistence as population or species under global change. However, long non-coding RNAs (lncRNAs) are scarcely studied especially in non-model organisms due to the lack of a reliable pipeline for their accurate identification and annotation. Here, we present a pipeline which uses a combination of alignment-dependent and independent methods for the identification of conserved and species-specific lncRNAs from RNA-Seq data. Validation of this pipeline was performed using existing RNA-Seq data from Acanthochromis polyacanthus brain tissue, identifying a total of 4,728 lncRNAs across the genome, the majority of which (3,272) are intergenic. To investigate the possible implications of these intergenic lncRNAs (lincRNAs), we estimated the expression changes of lincRNAs and coding genes in response to ocean acidification. We found lincRNAs which neighbour or possibly trans-regulate differentially expressed coding genes related to pH regulation, neural signal transduction and ion transport, which are known to be important in the response to ocean acidification in fish. Overall, this pipeline enables the use of existing RNA sequencing data to reveal additional underlying molecular mechanisms involved in the response to environmental changes by integrating the study of lncRNAs with gene expression.

molecular biology↗

bioRxiv2022

Modeling the effects of genetic and diet induced obesity on melanoma progression in zebrafish.

Obesity is a rising concern and associated with an increase in numerous cancers often in a sex-specific manner. Preclinical models are needed to deconvolute the intersection between obesity, sex, and cancer. We have generated a zebrafish system that can be used as a platform for studying these factors. We studied how germline overexpression of AgRP along with a high-fat diet (HFD) affects melanomas dependent on BRAFV600E. This revealed an increase in tumor incidence and area in male obese fish, but not females, consistent with the clinical literature. This is dependent on the somatic mutations, as male tumors generated with an RB1 mutation are sensitive to obesity, but this is not observed with PTEN. These data indicate that both germline and somatic mutations contribute to obesity related effects in melanoma. Given the rapid genetic tools available in the zebrafish, this provides a high-throughput system to dissect the interactions of genetics, diet, sex, and host factors in obesity-related cancers. Summary StatementDue to the rising incidence of obesity, there is a corresponding increased occurrence of obesity related cancers, which is often described to be dependent on sex. Here we developed a model to investigate the intersection between obesity, sex, and cancer.

cancer biology↗

bioRxiv2022

Lipid droplets are a metabolic vulnerability in melanoma

Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the pigmented cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved in human melanoma specimens. This state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt oxidative metabolism and slow melanoma growth in vivo. Because the pigmented cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.

cancer biology↗

bioRxiv2021

Electrical activity between skin cells regulates melanoma initiation

Oncogenes can only initiate tumors in certain cellular contexts, which is referred to as oncogenic competence. In melanoma, whether cells in the microenvironment can endow such competence remains unclear. Using a combination of zebrafish transgenesis coupled with human tissues, we demonstrate that GABAergic signaling between keratinocytes and melanocytes promotes melanoma initiation by BRAFV600E. GABA is synthesized in melanoma cells, which then acts on GABA-A receptors on keratinocytes. Electron microscopy demonstrates synapse-like structures between keratinocytes and melanoma cells, and multi-electrode array analysis shows that GABA acts to inhibit electrical activity in melanoma/keratinocyte co-cultures. Genetic and pharmacologic perturbation of GABA synthesis abrogates melanoma initiation in vivo. These data suggest that electrical activity across the skin microenvironment determines the ability of oncogenes to initiate melanoma.

cancer biology↗

bioRxiv2021

PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer

Identifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. Its depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. The enzymatic activity of PRMT1 is also required to stimulate the canonical Wnt pathway. Recently developed type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients, as well as the EGFR inhibitor, erlotinib. Therefore, targeting PRMT1 in combination with drugs used in the clinic may improve current treatments for TNBC patients. SignificanceThis study highlights the requirement of PRMT1 for breast cancer cell survival and demonstrates the potential of targeting type I PRMTs in combination with chemotherapies in triple-negative breast cancer.

cancer biology↗

bioRxiv2021

EROS-mediated control of NOX2 and P2X7 biosynthesis

EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase (OST) machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficient mouse and human primary cells. Accordingly, lack of EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation and possibly gene therapy.

immunology↗

bioRxiv2021

QPromoters: Sequence based prediction of promoter strength in Saccharomyces cerevisiae

Promoters play a key role in influencing transcriptional regulation for fine-tuning expression of genes. Heterologous promoter engineering has been a widely used concept to control the level of transcription in all model organisms. The strength of a promoter is mainly determined by its nucleotide composition. Many promoter libraries have been curated but few have attempted to develop theoretical methods to predict the strength of promoters from its nucleotide sequence. Such theoretical methods are not only valuable in the design of promoters with specified strength, but are also meaningful to understand the mechanism of promoters in gene transcription. In this study, we present a theoretical model to describe the relationship between promoter strength and nucleotide sequence in Saccharomyces cerevisiae. We infer from our analysis that the -49 to 10 sequence with respect to the Transcription Start Site represents the minimal region that can be used to predict the promoter strength. We present an online tool https://qpromoters.com/ that takes advantage of this fact to quickly quantify the strength of the promoters.

synthetic biology↗

bioRxiv2020

Do honey bee species differ in the odometer used for the waggle dance?

Honey bees estimate distances to food sources using image motion experienced on the flight path and they use this measure to tune the waggle phase duration in their dance communication. Most studies on the relationship between experienced optic flow and the dance-related odometer are based on experiments with Apis mellifera foragers trained into a small tunnel with black and white patterns which allowed quantifiable changes in the optic flow. In this study we determined the calibration curves for foragers of the two Asian honey bee species, A. florea and A. cerana, in two different natural environments with clear differences in the vegetation conditions and hence visual contrast. We found that the dense vegetation condition (with higher contrast) elicited a more rapid increase in the waggle phase duration with distance than the sparse vegetation in A. florea but not in A. cerana. Visual contrast did not affect the perception of the food reward, measured as the number of dance circuits produced per distance, in both species. Our findings suggest that contrast sensitivity of the waggle dance odometer, or other aspects of flight behaviour, might vary among honey bee species.

animal behavior and cognition↗

bioRxiv2019

Microgravity modulates effects of chemotherapeutic drugs on cancer cell migration

Microgravity or the condition of apparent weightlessness causes bone, muscular and immune system dysfunctions in astronauts following spaceflights. These organ and system-level dysfunctions correlate with changes induced at the single cell level both by simulated microgravity on earth as well as microgravity conditions in outer space (as in the international space station). Reported changes in single bone cells, muscle cells and white blood cells include structural/morphological abnormalities, changes in gene expression, protein expression, metabolic pathways and signaling pathways, suggesting that cells mount some response or adjustment to microgravity. However, the implications of such adjustments on many cellular functions and responses are not clear largely because the primary mechanism of gravity sensing in animal cells is unknown. Here we used a rotary cell culture system developed by NASA, to subject leukemic and erythroleukemic cancer cells to microgravity for 48 hours and then quantified their innate immune-response to common anti-cancer drugs using biophysical parameters and our recently developed quantum-dots-based fluorescence spectroscopy. We found that leukemic cancer cells treated with daunorubicin show increased chemotactic migration (p < 0.01) following simulated microgravity (g) compared to normal gravity on earth (1g). However, cells treated with doxorubicin showed enhanced migration both in 1g and following g. Our results show that microgravity modulates cancer cell response to chemotherapy in a drug-dependent manner. These results suggest using simulated microgravity as an immunomodulatory tool for the development of new immunotherapies for both space and terrestrial medicine.

biophysics↗

bioRxiv2019

Control of cytokinesis by β-adrenergic receptors indicates an approach for regulating cardiomyocyte endowment

ABSTRACT/SUMMARYOne million patients with congenital heart disease (CHD) live in the US. They have a lifelong risk of developing heart failure. Current concepts do not sufficiently address mechanisms of heart failure development specifically for these patients. We show that cardiomyocyte cytokinesis failure is increased in tetralogy of Fallot with pulmonary stenosis (ToF/PS), a common form of CHD. Labeling of a ToF/PS baby with isotope-tagged thymidine showed cytokinesis failure after birth. We used single-cell transcriptional profiling to discover that the underlying mechanism is repression of the cytokinesis gene ECT2, and show that this is downstream of {beta}-adrenergic receptors ({beta}-AR). Inactivation of the {beta}-AR genes and administration of the {beta}-blocker propranolol increased cardiomyocyte division in neonatal mice, which increased the endowment and conferred benefit after myocardial infarction in adults. Propranolol enabled the division of ToF/PS cardiomyocytes. These results suggest that {beta}-blockers should be evaluated for increasing cardiomyocyte division in patients with ToF/PS and other types of CHD.

cell biology↗

bioRxiv2018

Quantitative multi-locus metabarcoding and waggle dance interpretation reveal honey bee spring foraging patterns in Midwest agroecosystems

We explored the pollen foraging behavior of honey bee colonies situated in the corn and soybean dominated agroecosystems of central Ohio over a month-long period using both pollen metabarcoding and waggle dance inference of spatial foraging patterns. For molecular pollen analysis we developed simple and cost-effective laboratory and bioinformatics methods. Targeting four plant barcode loci (ITS2, rbcL, trnL and trnH), we implemented metabarcoding library preparation and dual-indexing protocols designed to minimize amplification biases and index mis-tagging events. We constructed comprehensive, curated reference databases for hierarchical taxonomic classification of metabarcoding data and used these databases to train the Metaxa2 DNA sequence classifier. Comparisons between morphological and molecular palynology provide strong support for the quantitative potential of multi-locus metabarcoding. Results revealed consistent foraging habits between locations and show clear trends in the phenological progression of honey bee spring foraging in these agricultural areas. Our data suggest that three key taxa, woody Rosaceae such as pome fruits and hawthorns, Salix, and Trifolium provided the majority of pollen nutrition during the study. Spatially, these foraging patterns were associated with a significant preference for forests and tree lines relative to crop fields and herbaceous land cover.

ecology↗