Biology subjects

Murthy, S.

Publications and source records attributed to Murthy, S..

At least 19 recordsLinked to original sources

bioRxiv2026

From Coral Color to Tissue Heating: How Host Pigments Redirect Light Within the Tissue

Coral host pigments strongly modify the internal light environment of corals, yet their influence on heat dissipation in coral tissue remains poorly understood. Here, we combined scalar irradiance and temperature microsensor measurements with mechanistic multiphysics modelling to quantify how chromoproteins (CPs) and fluorescent proteins (FPs) regulate light propagation and tissue heating in corals. Measurement-informed simulations of coupled radiative and heat transfer showed that high host pigment concentrations increase broadband scattering while strongly absorbing light within their characteristic spectral bands, reducing light penetration into deeper tissue layers and producing localized energy deposition. Under high symbiont densities, tissue heating was governed by absorption by both symbionts and host pigments, whereas in bleached corals, host pigments became the dominant source of heat generation. Heat generated by CP absorption was concentrated within the epidermis, while symbiont absorption caused deeper heating within the gastrodermis. Unlike CPs, FPs additionally redistributed a fraction of the absorbed photons through lower energy fluorescence emission, increasing scalar irradiance at longer wavelengths and shifting energy deposition deeper into the tissue, thereby enhancing subsurface heating relative to the corresponding non-fluorescent CP scenario. In the model, this pathway changes scalar irradiance and predicted energy deposition relative to the same FP parameterization with fluorescence disabled. The magnitude of this effect varied with FP concentration, spatial organization (granular or diffuse), and symbiont density. Model outputs were supported by surface light and temperature microsensor measurements across sampled coral phenotypes and symbiont densities. Together, our results demonstrate distinct modeled optical pathways for CPs and FPs that regulate not only light propagation but also the spatial distribution of heat generation within coral tissues. By balancing light attenuation, spectral redistribution, and heat generation, host pigmentation is thus likely to influence photoacclimation, bleaching susceptibility, and recovery of the coral-algal symbiosis.

biophysics↗

bioRxiv2026

Targeting collagen biosynthesis by small molecules inhibiting the function of the peptide-substrate-binding domain of collagen prolyl 4-hydroxylases

Collagen prolyl 4-hydroxylase (C-P4H) is an essential enzyme in collagen synthesis and known to be a potential target for drugs that prevent excess collagen formation. Currently known C-P4H inhibitors target the catalytic site of C-P4H, being analogues of 2-oxoglutarate (2OG). However, in mammalian cells there are many other 2OG-dependent dioxygenases with a highly similar catalytic domain, which limits the selective specificity of drugs targeting C-P4H activity. The peptide-substrate-binding (PSB) domain is unique for the C-P4H family and known to be important for the catalytic efficiency of C-P4H. Therefore, interfering with peptide binding to the PSB domain might allow more specific inhibition of the hydroxylation activity of C-P4Hs. We developed a robust FRET-based high-throughput screening assay (Z > 0.73) based on PSB-peptide interactions. This assay was used to screen a peptidomimetic library of 15614 compounds with the PSB domains of C-P4H isoforms I and II. A hit compound (OUL-PSBi-001) was identified with IC50s of 40 {micro}M and 62 {micro}M for PSB-I and PSB-II, respectively. We also showed that this compound indeed inhibits the catalytic activity of the full-length CP4H-I and -II. This FRET assay provides a new strategy for finding selective inhibitors for the treatment of fibrotic diseases and cancer.

molecular biology↗

bioRxiv2025

Enhancing Microalgal Growth through Integrated Computational Modeling and 3D Bioprinting

Efficient cultivation of microalgae for biofuel and bioproduct applications is often limited by suboptimal light distribution, poor mass transfer, and large land footprint requirements in conventional flat biofilm and open-pond systems. In this study, we combine computational modeling, 3D bioprinting, and experimental measurements to design and evaluate the role of different geometries for photosynthetic production in bioprinted microalgal constructs. Specifically, we investigate a perforated slab with channels (PS) and Vgroove structures, which show enhanced algal growth performance compared to flat slabs of the same volume and footprint. By integrating experimentally measured photosynthetic parameters into radiative transfer and oxygen diffusion-reaction simulations, we uncover the role of structure induced improvements in light penetration, surface area-to-volume ratio, and mass transfer dynamics driving increased algal growth and photosynthesis. Algal growth rates in printed PS and Vgroove geometries were 2.4 and 1.3 times higher, respectively, than in corresponding slab. These findings demonstrate the potential of engineered 3D bioprinted architectures to optimize photosynthetic efficiency and growth rates while minimizing spatial footprint, paving the way for compact, high-throughput bioreactors for sustainable algal cultivation. Beyond biofuel production, these microalgal systems enable sustainable CO2 capture and utilization.

bioengineering↗

bioRxiv2025

Epigenetic Reprogramming of Host Chromatin by the Transforming Parasite Theileria annulata

Theileria annulata, a transforming apicomplexan parasite, extensively reprograms the chromatin architecture of bovine leukocytes to facilitate infection and cellular transformation. To elucidate the underlying epigenetic mechanisms, we characterized the chromatin landscape of infected lymphocytes using integrated proteomic, imaging, and functional assays. Our findings reveal that T. annulata lacks the DNA damage marker {gamma}H2A.X and its associated SQ/TQ motif, indicating an evolutionary divergence from canonical DNA repair signalling pathways. High-resolution profiling of histone post-translational modifications (PTMs) demonstrated distinct nuclear compartmentalization, with host (H3K27me3, H3K9me1/2), parasite-predominant modifications (H3K4me3, H3K18me1, H3K27ac, H3K9ac, and H3K36me3), and shared modifications (e.g., H3K4me1/2, H3K36me2, H4K5/8/12/16ac, H3K9me3 and H4K91Ac) suggesting a coordinated epigenetic strategy driving host cell programs to sustain proliferation and survival. Our study delineates a novel host-parasite epigenetic interface, positioning T. annulata as a unique model of epigenetic parasitism. By bridging parasitology and cancer epigenetics, these findings unveil new therapeutic opportunities targeting chromatin vulnerabilities in parasite-induced transformation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/684985v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1bd0e05org.highwire.dtl.DTLVardef@e37ea4org.highwire.dtl.DTLVardef@18f78d5org.highwire.dtl.DTLVardef@460eb4_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Functional imaging of 3D bioprinted microalgal constructs and simulation of their photosynthetic performance

The intricate three dimensional architecture at different spatial length scales affects the functionality and growth performance of immobilized photosynthesizing cells in biofilms and bioprinted constructs. Despite the tremendous potential of 3D bioprinting in precisely defining sample heterogeneity and composition in spatial context, cell metabolism is mostly measured in media surrounding the constructs or by destructive sample analyses. The exploration and application of non-invasive techniques for monitoring physico-chemical microenvironments, growth and metabolic activity of cells in 3D printed constructs is thus in strong demand. Here, we present a pipeline for the fabrication of 3D bioprinted microalgal constructs with a functionalized gelatin methacryloyl (GelMA)-based bioink for imaging O2 dynamics within bioprinted constructs, as well as their characterization using various, non-invasive functional imaging techniques and numerical simulation of their photophysiological performance. This fabrication, imaging and simulation pipeline now enables investigation of the effect of structure and composition on photosynthetic efficiency of bioprinted constructs with microalgae or cyanobacteria. It can facilitate designing efficient construct geometries for enhanced light penetration and improved mass transfer of nutrients, CO2 or O2 between the 3D printed construct and the surrounding medium, thereby providing a mechanistic basis for the design of more efficient artificial photosynthetic systems.

bioengineering↗

bioRxiv2025

Engineered spermidine-secreting Saccharomyces boulardii ameliorate colitis and colon cancer in mice

Experimental studies suggest that the probiotic yeast Saccharomyces boulardii can mitigate the symptoms of inflammatory bowel disease. However, these results are equivocal and S boulardii probiotic therapy has not gained widespread acceptance in clinical practice. To assess whether the therapeutic properties of S boulardii might be improved upon, we engineered S boulardii to overproduce and secrete spermidine, a pro-regenerative natural metabolite. We employed CRISPR gene deletion and transposon-mediated gene integration to manipulate expression of key enzymes in the polyamine synthetic and transport pathways. We tested the engineered yeast by oral gavage of mice treated with azoxymethane and dextran sulfate sodium to induce chronic colitis and colon cancer. We demonstrate that oral delivery of spermidine-secreting S boulardii in mice populates the gastrointestinal tract with viable spermidine-secreting S boulardii cells and raises free spermidine levels in the gastrointestinal tract. Strikingly, spermidine-secreting S boulardii strains were significantly more effective than wild-type S boulardii in reducing dextran sulfate sodium-induced colitis as well as colitis-associated colon cancer in mice. These results suggest that in situ spermidine secretion by engineered synthetic biotic yeast strains may be an effective and low-cost therapy to mitigate inflammatory bowel disease and colon cancer.

cancer biology↗

bioRxiv2024

Direct expression of CPT1a enables a high throughput platform for the discovery of CPT1a modulators

Carnitine palmitoyltransferase 1 (CPT1), which catalyzes the rate-limiting step of fatty acid oxidation, has been implicated in therapeutic approaches to several human diseases characterized by aberrant lipid metabolism. Isoform-specific quantification of CPT1 activity is essential in the characterization of small molecule inhibitors of CPT1, but several existing means to quantify enzymatic activity, including the use of radioisotope labeled carnitine, are not amenable to scalable, high throughput screening. Here, we demonstrate that mitochondrial extracts from Expi293 cells transfected with a CPT1a plasmid are a reliable and robust source of catalytically active human CPT1. Moreover, with a source of catalytically active enzyme in hand, we modified a previously reported colorimetric method of coenzyme A (CoA) easily scalable to a 96-well format for the screening of CPT1a inhibitors. This assay platform was validated by two previously reported inhibitors of CPT1a: R-etomoxir and perhexiline. To further demonstrate the applicability of this method in small molecule screening, we prepared and screened a library of 87 known small molecule APIs, validating the inhibitory effect of chlorpromazine on CPT1. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/628575v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1f69f0corg.highwire.dtl.DTLVardef@43eb95org.highwire.dtl.DTLVardef@11fa21corg.highwire.dtl.DTLVardef@1cbe405_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Phosphorylation Toggles the SARS-CoV-2 Nucleocapsid Protein Between Two Membrane-Associated Condensate States

The Nucleocapsid protein (N) of SARS-CoV-2 plays a critical role in the viral lifecycle by regulating RNA replication and packaging the viral genome. N and RNA phase separate to form condensates that may be important for these functions. Both functions occur at membrane surfaces, but how N toggles between these two membrane-associated functional states is unclear. Here, we reveal that phosphorylation switches how N condensates interact with membranes, partly by modulating condensate material properties. Phosphorylated N forms liquid condensates that wet membranes, reminiscent of Ns role in RNA replication. In contrast, unmodified N forms viscoelastic condensates that can be engulfed by membranes, evoking viral genome packaging. These results suggest that phosphorylation serves as a regulatory switch within the viral replication cycle by modulating Ns association with membranes. We gained mechanistic insight through structural analysis and molecular simulations, which suggest phosphorylation induces a conformational change that softens condensate material properties. Our studies also show that phosphorylation alters Ns interaction with viral membrane proteins. Together, our findings uncover a novel aspect of SARS-CoV-2 biology by identifying membrane association as a key feature of N condensates and providing mechanistic insights into the regulatory role of phosphorylation. Understanding this mechanism suggests potential therapeutic targets for COVID infection.

biophysics↗

bioRxiv2024

Framework for Martini-based Coarse-grained Model of Enzymes: Model Development and Experimental Validation

Recent experiments have shown that enzyme activity can preserved in harsh environments by complexing enzyme with polymer into a Protein-Polymer Hybrid (PPH). In a successful PPH, heteropolymer strands bind to the enzyme surface and restrain the folded protein without adversely affecting the binding and active sites. It is believed that hybridization is driven by non-covalent interactions at the enzyme surface including hydrophobicity and electrostatics. Molecular modeling of these interactions is not practical at the all-atom scale due to the long timescales and large particle counts needed to characterize binding. Protein structure at the scale of amino acid residues is parsimoniously represented by a coarse-grained model in which one particle represents several atoms, significantly reducing the cost of simulation. In this study we present two coarse-grained enzyme models - lipase and dehalogenase - prepared using a top-down modeling strategy. We simulate each enzyme in aqueous solution and calculate statistics of protein surface features and shape descriptors. The values from the coarse-grained data are compared with the same calculations performed on all-atom reference systems, revealing key similarities of surface chemistry at the two scales. Structural measures are calculated from the all-atom reference systems and compared with estimates from small-angle X-ray scattering (SAXS) experiments, with good agreement between the two. The described procedures of modeling and analysis comprise a framework for the development of coarse-grained models of protein surfaces with validation to experiment.

biophysics↗

bioRxiv2024

The Hox Gene, abdominal A controls timely mitotic entry of neural stem cell and their growth during CNS development in Drosophila

Cell size is a critical determinant of its function and physiology. In this study, we investigated the regulation of stem cell size during Drosophila central nervous system (CNS) development and its association with cell fate. We note that neural stem cells (NSCs) in different regions of ventral nerve cord increase their size at different rates. The, thoracic NSCs grow at a faster rate compared to those in the abdominal region. We show that in addition to its role in apoptosis and nervous system remodeling, abdA also plays an instructive role in regulating the rate of NSC size increase and its timely entry into mitosis. Weak expression of abdA in larval abdominal NSCs was sufficient to retard the rate of their size increase and delay their mitotic entry compared to thoracic NSCs. Knockdown of abdA in NSCs enhances their rate of size increase leading to early mitotic entry, while ectopic abdA expression in thoracic NSCs reduces their size and delays their mitotic entry. We show that abdA-mediated NSC size regulation acts downstream of nutrition-induced NSC activation, which fine-tunes the stem cell potential spatiotemporally. This study highlights the instructive role of abdA in regulating various fates of larval NSCs during CNS patterning. Significance statementO_LIUnderstanding the upstream regulation of various aspects of the cell cycle is crucial; however, the influence of cell size on this process remains largely unknown. C_LIO_LIWe found an instructive role for the Hox gene abdominal A in maintaining the small size of neural stem cells (NSCs) and in regulating the time and rate of mitosis. C_LIO_LIThis mechanism is crucial because it helps NSCs generate the necessary number of neurons at an appropriate developmental stage, thereby contributing to proper central nervous system patterning. C_LI

developmental biology↗

bioRxiv2024

Culture Conditions Differentially Regulate the Inflammatory Niche and Cellular Phenotype of Tracheo-Bronchial Basal Stem Cells

Human bronchial epithelial cells (HBECs) derived from the tracheo-bronchial regions of human airways provide an excellent in vitro model for studying pathological mechanisms and evaluating therapeutics in human airway cells. This cell population comprises a mixed population of basal cells (BCs), the predominant stem cell in airways capable of both self-renewal and functional differentiation. Despite their potential for regenerative medicine, BCs exhibit significant phenotypic variability in culture. To investigate how culture conditions influence BC phenotype and function, we expanded three independent BC isolates in three media, airway epithelial cell growth medium (AECGM), dual-SMAD inhibitor (DSI)-enriched AECGM, and Pneumacult Ex plus (PEx+). Extensive RNA sequencing, immune assays and electrical measurements revealed that PEx+ media significantly drove cell proliferation and a broad pro-inflammatory phenotype in BCs. In contrast, BCs expanded in AECGM, displayed increased expression of structural and extracellular matrix components at high passage. Whereas culture in AECGM increased expression of some cytokines at high passage, DSI suppressed inflammation altogether thus implicating TGF-{beta} in BC inflammatory processes. Differentiation capacity declined with time in culture irrespective of expansion media except for PLUNC expressing secretory cells that were elevated at high passage in AECGM and PEx+ suggestive of an immune modulatory role of PLUNC in BCs. These findings underscore the profound impact of media conditions on inflammatory niche and function of in vitro expanded BCs. The broad pro-inflammatory phenotype driven by PEx+ media, in particular, should be considered in the development of cell-based models for airway diseases and therapeutic application. NEW & NOTEWORTHYAirway basal cells, vital for airway regeneration and potential therapies, show significant changes based on culture conditions. Our study reveals that media composition and culture duration greatly affect basal cell properties with profound changes in the pro-inflammatory phenotype and extracellular matrix deposition driven by changes in growth conditions. These results underscore the critical impact of culture conditions on BC phenotype, influencing cell-based models for airway disease research and therapy.

cell biology↗

bioRxiv2024

Whole genome sequencing and comparative genomic studies of Priestia filamentosa JURBA-X for its drought-tolerance, plant-growth promotion, and fluorescent characteristics

Priestia filamentosa JURBA-X is a nonmotile, endospore-forming, and Gram-positive bacterium isolated from a rhizosphere soil sample of groundnut fields in Andhra Pradesh, India, during summer. JURBA-X exhibits chains of filamentous morphology with vibrant yellow fluorescence. It shows tolerance to drought stress, phosphate solubilization, siderophore production, and antibacterial activity. 16s rRNA and single-copy orthologous DNA gyrase subunit B-based phylogenies suggested its closeness with Priestia filamentosa spp., leading to its classification as P. filamentosa JURBA-X. The whole genome was assembled into 5,113,908 bp, distributed across 55 contigs with a GC content of 36.59% and 5,352 protein-coding genes. Genome-genome distance and average nucleotide identity confirmed its designation as a novel strain within P. filamentosa. Assignment of genes/proteins in diverse functions such as drought tolerance, plant growth promotion (PGP), lantibiotics, polyketides, vitamin synthesis, siderophores production, and phosphate solubilization highlight its potential utilization in agriculture as a PGPR and industrial production of antimicrobial agent, vitamins, and biopolymers. Our research concluded that the fluorescence exhibited by JURBA-X is potentially attributed to the production of resistomycin, which might have been horizontally transferred from Streptomyces resistomycificus as inferred by the homology of resistomycin (rem) biosynthesis cluster genes.

microbiology↗

bioRxiv2023

Light management by algal aggregates in living photosynthetic hydrogels.

Rapid progress in algal biotechnology has triggered a growing interest in hydrogel-encapsulated microalgal cultivation, especially for the engineering of functional photosynthetic materials and biomass production. An overlooked characteristic of gel-encapsulated cultures is the emergence of cell aggregates, which are the result of the mechanical confinement of the cells. Such aggregates have a dramatic effect on the light management of gel-encapsulated photobioreactors and hence strongly affect the photosynthetic outcome. In order to evaluate such an effect, we experimentally studied the optical response of hydrogels containing algal aggregates and developed optical simulations to study the resultant light intensity profiles. The simulations are validated experimentally via transmittance measurements using an integrating sphere and aggregate volume analysis with confocal microscopy. Specifically, the heterogeneous distribution of cell aggregates in a gel matrix can increase light penetration while alleviating photoinhibition compared to a flat biofilm. Finally, we demonstrate that light harvesting efficiency can be further enhanced with the introduction of scattering particles within the hydrogel matrix, leading to a four-fold increase in biomass growth. Our study, therefore, highlights a new strategy for the design of spatially efficient photosynthetic living materials that have important implications for the engineering of future algal cultivation systems. Significance StatementThe ability to cultivate microalgae at scale efficiently would allow more sustainable production of food and food additives. However, efficient growth of microalgae requires optimised light conditions, which are usually challenging to obtain using biofilm cultivations mode: as the outer layer of cells are necessarily more exposed to incoming light than the inner layer, posing the problem of photoinhibition on the outer cells receiving too much light, and shading the ones below. Here we study both experimentally and numerically, how microalgae aggregates growing in the confinement of a hydrogel can provide an improved light distribution and therefore biomass growth is maximised. This study proposes new strategies on how to engineer future photobioreactors.

plant biology↗

bioRxiv2023

Sorafenib inhibits invasion of multicellular organoids that mimic Lymphangioleiomyomatosis nodules.

Lymphangioleiomyomatosis (LAM) is a progressive lung disease with limited treatments, largely due to an incomplete understanding of its pathogenesis. Lymphatic endothelial cells (LECs) invade LAM cell clusters, which include HMB-45-positive epithelioid cells and smooth muscle -actin-expressing LAM-associated fibroblasts (LAMFs). Recent evidence shows that LAMFs resemble cancer-associated fibroblasts, with LAMF-LEC interactions contributing to disease progression. To explore these mechanisms, we used spatial transcriptomics on LAM lung tissues and identified a gene cluster enriched in kinase signaling pathways linked to myofibroblasts and co-expressed with LEC markers. Kinase arrays revealed elevated PDGFR and FGFR in LAMFs. Using a 3D co-culture spheroid model of primary LAMFs and LECs, we observed increased invasion in LAMF-LEC spheroids compared to non-LAM fibroblasts. Treatment with sorafenib, a multikinase inhibitor, significantly reduced invasion, outperforming Rapamycin. We also confirmed TSC2-null AML cells as key VEGF-A secretors, which was suppressed by sorafenib in both AML cells and LAMFs. These findings highlight VEGF-A and bFGF as potential therapeutic targets and suggest multikinase inhibition as a promising strategy for LAM. One Sentence SummaryUsing 3D spheroids and spatial transcriptomics, we identified LAMFs and LECs as key contributors to LAM, with bFGF and VEGF-A as potential therapeutic targets

cell biology↗

bioRxiv2023

Zoledronic acid improves bone quality and muscle function in a high bone turnover state

SUMMARYZoledronic acid (ZA) prevents muscle weakness in mice with bone metastases; however, its role in muscle weakness in non-tumor-associated metabolic bone diseases and as an effective treatment modality for the prevention of muscle weakness associated with bone disorders, is unknown. We demonstrate the role of ZA-treatment on bone and muscle using a mouse model of accelerated bone remodeling, which represents the clinical manifestation of non-tumor associated metabolic bone disease. ZA increased bone mass and strength and rescued osteocyte lacunocanalicular organization. Short-term ZA treatment increased muscle mass, whereas prolonged, preventive treatment improved muscle mass and function. In these mice, muscle fiber-type shifted from oxidative to glycolytic and ZA restored normal muscle fiber distribution. By blocking TGF{beta} release from bone, ZA improved muscle function, promoted myoblast differentiation and stabilized Ryanodine Receptor-1 calcium channel. These data demonstrate the beneficial effects of ZA in maintaining bone health and preserving muscle mass and function in a model of metabolic bone disease. Context and significanceTGF{beta} is a bone regulatory molecule which is stored in bone matrix, released during bone remodeling, and must be maintained at an optimal level for the good health of the bone. Excess TGF{beta} causes several bone disorders and skeletal muscle weakness. Reducing excess TGF{beta} release from bone using zoledronic acid in mice not only improved bone volume and strength but also increased muscle mass, and muscle function. Progressive muscle weakness coexists with bone disorders, decreasing quality of life and increasing morbidity and mortality. Currently, there is a critical need for treatments improving muscle mass and function in patients with debilitating weakness. Zoledronic acids benefit extends beyond bone and could also be useful in treating muscle weakness associated with bone disorders.

cancer biology↗

bioRxiv2023

Live tracking of a plant pathogen outbreak reveals rapid and successive, multidecade episome reduction

Quickly understanding the genomic changes that lead to pathogen emergence is necessary to launch mitigation efforts and reduce harm. Often the evolutionary events that result in an epidemic typically remain elusive long after an outbreak, which is particularly true for plant pathogens. To rapidly define the consequential evolutionary events result in pathogen emergence, we tracked in real-time a 2022 bacterial plant disease outbreak in US geranium (Pelargonium x hortorum) caused by Xhp2022, a novel lineage of Xanthomonas hortorum. Genomes from 31 Xhp2022 isolates from seven states showed limited chromosomal variation, and all contained a single plasmid (p93). Time tree and SNP whole genome analysis estimated that Xhp2022 emerged in the early 2020s. Phylogenomic analysis determined that p93 resulted from cointegration of three plasmids (p31, p45, and p66) present in a 2012 outbreak. p31, p45 and p66 were individually found in varying abundance across X. hortorum isolates from historical outbreaks dating to 1974 suggesting these plasmids were maintained in the broader metapopulation. p93 specifically arose from two co-integration events from homologous and Tn3 and XerC-mediated site-specific recombination. Although p93 suffered a 49kb nucleotide reduction, it maintained critical fitness gene functions encoding, for example, metal resistance and virulence factors, which were likely selected by the ornamental production system. Overall we demonstrate how rapid sequencing of current and historical isolates track the evolutionary history of an emerging, ongoing threat. We show a recent, tractable event of genome reduction for niche adaptation typically observed over millenia in obligate and fastidious pathogens. SignificanceGenome-resolved epidemiology is rapidly changing how we track pathogens in real-time to support stakeholders and health. This research highlights how we responded to a current disease outbreak of geranium. Our work revealed that a new group of the bacterial plant pathogen Xanthomonas horotrum emerged in 2022 as a result of a recent genome reduction. We determined that three distinct plasmids were present in the broader X. hortorum metapopulation since 1974. In 2012, the three plasmids were altogether present in individual isolates; then in 2022, all three plasmids co-integrated while maintaining critical fitness genes but losing extraneous genomic material. This parallels genome efficiency and reduction that we see across millenia or even millions of years with obligate parasites with increased niche-specificity.

microbiology↗

bioRxiv2023

Expansion of triplet nucleotide repeats in primates and other vertebrates: an evolutionary perspective

Triplet nucleotide repeat (TNR) expansion has been linked to more than 40 inheritable neurological, neuromuscular and neurodegenerative disorders. Increase in copy number beyond a threshold causes further rapid expansion of the repeats, leading to instability and disease via gain/loss of function, toxic RNA products or chromosome instability. An analysis of these repeat regions across vertebrates shows that these repeats have consistently either arisen late or have increased in copy number in vertebrates, most significantly in primates and particularly in humans. Many of the known diseases have neurological basis, suggests positive selection of these repeats for neuronal function. Late occurrence of the diseases implicates a lack of negative selection. This evolutionary trade-off, a higher neuronal capability at the cost of disease susceptibility, is further supported by the observation that most of the genes associated with TNR expansion diseases have neuronal function.

genomics↗

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↗