Biology subjects

Miller, J.

Publications and source records attributed to Miller, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Growth-state as a determinant of in vivo virulence of Mycoplasma pneumoniae

Mycoplasma pneumoniae is a leading cause of community acquired pneumonia and bronchitis in people, particularly children and young adults. Like many bacterial pathogens, M. pneumoniae can grow in biofilm towers on both biotic and abiotic surfaces. Current models indicate that planktonic M. pneumoniae are simply individual cells that are dispersed from biofilm towers due to physical shear forces, and do not represent a bona fide planktonic growth state. However recent data indicate that these fractions may be physiologically distinct and may differentially influence disease outcome. We observed that experimental infection of mice with inoculum containing both adherent and non-adherent fractions of M. pneumoniae produced more severe lung pathology than inoculum prepared from M. pneumoniae adherent biofilms alone. Direct comparison of experimental infection with titer matched non-adherent (P-Mp) and adherent (B-Mp) fractions revealed that P-Mp produces more severe lung pathology compared to infection with B-Mp. Furthermore, experimental infection with a lower dose of P-Mp resulted in similar lung pathology relative to B-Mp infected mice. This increase in pathology was not associated with differences in bacterial burden, bacterial dispersal during inoculum preparation, nor due to differences in the phenotype of host immune responses. Comparative proteomics revealed that certain known and putative virulence factors associated with immune evasion are upregulated in P-Mp, potentially explaining the difference in virulence between the two fractions. Furthermore, comparative proteomics revealed distinct metabolic phenotypes between the two fractions, consistent with distinct planktonic and biofilm growth states, indicating that P-Mp likely represents a bona fide planktonic growth state. Collectively, these data implicate the growth state of M. pneumoniae as a determinant of in vivo virulence for this atypical human pathogen.

microbiology↗

bioRxiv2026

An open field phenomics resource for multimodal maize yield prediction across divergent environments

Temporal drone phenotyping captures crop development, but irregular flight schedules complicate comparisons across environments. We release curated imagery from 356 flights across 19 Genomes to Fields environments containing 1,180 maize (Zea mays L.) hybrids. To evaluate its utility, we integrated functional principal components of vegetation index and weather trajectories with genomic information. Combinined genomic and phenomic kernels improved yield prediction, reaching correlations up to r = 0.501 for held-out hybrids in environments represented in training and 0.408 when environments were also withheld. Accumulated growing degree days offered no consistent predictive advantage over days after planting, and weather contributed modest, task-dependent gains. A transformer neural process learned directly from irregular observations, serving as a novel application of neural process models in agriculture. Mapping vegetation index functional principal components identified recurrent quantitative trait loci on chromosomes 3 and 7. This resource and its reproducible analyses guide the use of temporal spectral data for crop prediction and genetic discovery.

plant biology↗

bioRxiv2026

DNA Sequence-Programmed Protein Coronas Determine Intracellular Fate and Proteostatic Stress of Carbon Nanotubes

Single-walled carbon nanotubes (SWCNTs) show promise for optical biosensing, imaging, and drug delivery, but turning them into safe, precision nanomedicine tools requires understanding how nanotube surface chemistry dictates recognition and processing by cells. Like other nanomaterials, carbon nanotubes acquire a biomolecular corona on contact with biological fluids, and corona identity is increasingly recognized as central to sensor performance and drug delivery efficacy. However, whether corona identity also governs the intracellular fate of carbon nanotubes remains largely unknown. Here, we show that the single-stranded DNA wrapping of (6,5)-enriched single-walled carbon nanotubes reprograms their protein corona, intracellular trafficking, and macrophage response. By profiling (AT)15, (GT)15, and (CT)15 wrapped SWCNTs, we show that the wrapping sequence programs both the protein corona and the resulting proteostatic stress on macrophages. Photoluminescence imaging and confocal Raman measurements reported that (AT)15 is internalized the most yet leaves the proteome and nanotube structure largely undisturbed, whereas (CT)15, taken up the least, undergoes the most aggressive intracellular degradation and drives the highest oxidative and proteostatic stress. Corona proteomics indicated that all three tested nanotubes form coronas with distinct functional identities that are responsible for divergent intracellular routes. Time-resolved intracellular proteomics combined with functional assays resolved how the host cell reorganizes its biomolecular complexity over time, including oxidative outputs, aside from a sequence-independent core response involving particle engagement, phagosomal sorting, and lysosomal processing. These findings provide mechanistic insight into nanomaterial-cell interactions and the wrapping sequence as a tunable, nucleotide-level design handle for controlling the intracellular fate of carbon nanomaterials, with potential implications for safe and effective nanomedicine platforms.

bioengineering↗

bioRxiv2026

The Prefrontal Cortex Organizes Visual Evidence by Representational Abstraction

Perceptual decisions often depend on both lower-level visual features and higher-level object representations, yet natural images entangle these levels of abstraction. We used deep neural network features to dissociate lower- and higher-level visual similarity during a naturalistic image-similarity judgment task. Participants relied on both forms of evidence, with greater weighting of higher-level similarity. Across prefrontal cortex, visual evidence was systematically organized by representational level: lower- and higher-level similarity were expressed in distinct prefrontal regions during comparison and remained spatially differentiated as they were transformed into decision signals. This organization was behaviorally relevant, with prefrontal activation predicting which level of evidence guided choice when the two conflicted. Together, these findings identify representational level as an organizing principle of prefrontal cortex during visual decisions.

neuroscience↗

bioRxiv2026

Augmenting Radiation Sensitivity by Targeting PAR-Dependent Replication Fork Vulnerability in IDH-Mutant Glioma

Mutations in isocitrate dehydrogenase 1 (IDH1) drive the early stages of gliomagenesis while simultaneously imposing replication stress that creates targetable vulnerabilities. Using both in vitro and in vivo models, we show that inhibition of poly(ADP-ribose) glycohydrolase (PARG) induces a poly(ADP-ribose) (PAR)-dependent augmentation of radiosensitivity in IDH1-mutant glioma cells. Metabolic repletion of NAD+ fails to rescue this effect, indicating that the vulnerability cannot be explained solely by NAD+ depletion. Instead, PARG inhibition profoundly alters replication fork progression and S-phase kinetics in IDH1-mutant cells. Mechanistically, ionizing radiation preferentially activates replication fork-associated damage response proteins DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and X-ray repair cross-complementing protein 1 (XRCC1) in IDH1-mutant cells, a response partially reversed by pharmacologic inhibition of mutant IDH1. Importantly, pharmacologic inhibition of DNA-PKcs with AZD7648 during irradiation disrupts fork-associated repair signaling and markedly enhances cytotoxicity in IDH1-mutant glioma models. Together, these findings identify a PAR-dependent replication fork vulnerability that can be therapeutically exploited to selectively enhance radiosensitivity in IDH1-mutant gliomas. Statement of significanceIDH-mutant gliomas harbor intrinsic replication stress yet lack targeted radiosensitization strategies. We identify a PAR-dependent replication fork vulnerability in which disruption amplifies radiation cytotoxicity by deregulating S-phase fork signaling. Pharmacologic DNA-PKcs inhibition exploits this dependency, providing a genotype-selective approach to enhance radiotherapy in IDH-mutant glioma.

cancer biology↗

bioRxiv2026

Structure-affinity correlations and separable optical activity in carbon nanotube protein coronas

Biomolecular corona on nanoparticle surfaces enriches low-abundance proteins and compresses the dynamic range of the plasma proteome. Single-walled carbon nanotubes are particularly attractive because their surface chemistry is highly tunable, and their near-infrared fluorescence directly reports corona modulation. However, how surface chemistry shapes the corona and how the corona relates to the fluorescence response remain unclear. We profiled protein enrichment patterns and the resulting fluorescence in a library of 25 chemically modified carbon nanotubes by quantitative proteomics and near-infrared fluorescence spectroscopy. We found that polymer and quantum-defect chemistry orthogonally modulate corona composition and dispersion forces are the dominant, universal driver of protein-nanotube binding. Proteomics and fluorescence correlation analyses indicate that enrichment and fluorescence response are partially decoupled. A subset of corona proteins stays optically silent, but where responses occur, enriched proteins respond at lower, physiologically relevant ranges than depleted ones. Our findings inform design principles for carbon nanomaterial-based sensors and biomarker discovery platforms.

biochemistry↗

bioRxiv2026

Transient MYC Mimicking the Exercise Response Orchestrates Multifaceted Skeletal Muscle Adaptations

Despite decades of study, MYCs physiological role in adult tissues remains obscured by the models used to investigate it. Most work relies almost exclusively on chronic or constitutive MYC induction that recapitulates the sustained activity found in tumorigenesis and expectedly produces pathological outcomes. What has gone largely untested is how MYC operates when induced in a controlled and physiologically relevant manner, as it is during adaptive processes such as exercise. Using a recombination-independent strategy in adult skeletal muscle, transient MYC bursts drive coordinated hypertrophic-metabolic reprogramming followed by a shift in myosin fiber type, recapitulating adaptations characteristic of concurrent endurance and resistance training. A single pleiotropic transcription factor governing several aspects of muscle health reframes perspectives on a gene understood almost entirely in the context of pathology. We uncover a previously unrecognized muscle-specific role for MYC in controlling muscle cell composition and present a multi-timepoint multi-omic resource for interrogating MYC: data.myoanalytics.com/study/myc_transient/gene.

Cell Biology↗

bioRxiv2026

LOESS and DE-SWAN can induce artifactual "waves" of molecular aging

A growing body of literature has investigated the relationship between age and biomolecular changes, leading to conclusions that aging occurs in discrete molecular "waves." Data summary tools such as LOESS and sliding window analyses like DE-SWAN are common approaches that have gained acceptance in recent years. We demonstrate via simple simulations that these tools can identify non-linear patterns of aging where they do not exist. Specifically, we show that (i) clustering of molecular trajectories using LOESS can lead to artifactual characteristic patterns of molecular aging, (ii) "waves" of aging identified using the combination of LOESS and DE-SWAN in real data are not robust to changes in the underlying age distribution and are not supported by valid permutation testing, and (iii) DE-SWAN alone can generate pronounced "waves" of nonlinear molecular aging in linear data due to differences in statistical power along the age continuum. Our results specifically challenge the statistical support for discrete aging crests inferred in the literature, but do not rule out nonlinear molecular aging or age-associated transitions that may be detectable using other cohorts and statistical models.

bioinformatics↗

bioRxiv2026

Engineering Carbon Nanotube Quantum Well Defects with Recognition Tripeptides for Optical Detection of Extracellular Vesicles in Plasma

Extracellular vesicles (EVs) carry molecular signatures of their originating cells and have thus emerged as promising biomarkers. However, their clinical utility remains limited due to their low abundance and the modest sensitivity of current EV detection methods in complex biological environments. Here, we present a quantum well defect functionalized carbon nanotube sensor coupled with integrin-recognition RGD tripeptide for EV detection in human plasma. Leveraging the abundance of integrins on EV surfaces, we targeted 5{beta}1, V{beta}1, and V{beta}3 subtypes. The nanosensor exhibited robust hypsochromic shifts in defect emission upon integrin binding, achieving sub-picomolar detection limits for integrin subunits and quantifying EVs at concentrations as low as 104 EVs{middle dot}mL-1 for glioblastoma, ovarian cancer, and fibroblast cell-derived EV types. Molecular dynamics simulation indicated that integrin docking at the RGD-coupled quantum defect can substantially reshape the interfacial environments of the quantum defects, explaining the high sensitivity in EV detection in complex biological media. Finally, transmembrane protein analysis validated the expression of surface integrins across the tested EV types. The modular nanosensor construct can be targeted to detect disease-associated EV subpopulations, advancing EV-based diagnostics.

biochemistry↗

bioRxiv2026

Coevolution of Species' Borders: Interactions Between Interspecific Competition, Gene Flow, and Matching Habitat Choice

Existing theory examining the coevolutionary dynamics of species range borders assumes random dispersal, which causes maladaptive gene flow from the range core to the range margins and contributes to the formation of range limits. However, dispersal is unlikely to be random for many organisms in nature, calling into question existing theoretical predictions. For example, if individuals exhibit phenotype-dependent adaptive dispersal strategies such as matching habitat choice, then the resulting adaptive gene flow toward species range margins could facilitate range expansions and potentially prevent the formation of range limits by interspecific competition. To test this idea, we use a comprehensive mathematical model to develop a quantitative theory of range border coevolution that incorporates phenotype-optimal dispersal--a particular form of matching habitat choice in which individuals follow the gradient in an environmental optimum phenotype to settle in the habit best suited for their phenotype. We find that instead of preventing competitively formed range limits, adaptive dispersal leads to sharper range limits and reduced character displacement in sympatry. These differences are particularly remarkable when natural selection is weak, when individuals are specialized in their resource use, or when individuals are highly sensitive to environmental conditions. We show that matching habitat choice causes backward edge-to-core movements which dynamically interact with the effects of interspecific competition to establish the range limits. Thus, the formation of range limits by interspecific competition is robust to assumptions about individual dispersal. Further, our results identify the competitive advantage of evolving matching habitat choice in steep environmental gradients, especially for slowly-growing species in rapidly fluctuating climates.

ecology↗

bioRxiv2026

Environmental control of morphological color changes in the Bigfin Reef Squid, Sepioteuthis lessoniana

Phenotypic plasticity enables organisms to adjust their traits in response to environmental conditions, yet studies of animal coloration--particularly in cephalopods--have largely focused on rapid neural control while overlooking slower, substrate-level changes. Here, we investigate whether morphological color change contributes to phenotypic plasticity in the bigfin reef squid (Sepioteuthis lessoniana). Hatchlings were reared in contrasting light (white) and dark (black) environments for 14 weeks, and chromatophore organization was quantified across developmental stages (4, 9, and 14 weeks) and body regions (dorsal and ventral) using high-resolution imaging and automated analysis. We find that environmental context and age interact to shape both the density and size of black, yellow, and red chromatophores, revealing a consistent trade-off between chromatophore number and expansion. Black-reared individuals maintain higher chromatophore densities, whereas white-reared individuals exhibit fewer but larger cells, particularly at later developmental stages. These effects are region-specific and align with the emergence of countershading, suggesting ecological tuning of pigmentation architecture. Our results demonstrate that the cellular substrate underlying color change is itself plastic and dynamically remodeled across development. We propose a hierarchical model in which slow morphological plasticity defines the functional limits of rapid neural color change. This work expands current frameworks of cephalopod coloration by integrating developmental, environmental, and cellular mechanisms, and highlights the importance of multi-timescale plasticity in adaptive visual signaling.

ecology↗

bioRxiv2026

Antioxidant defenses of Francisella tularensis perturb Aim2 Inflammasome Activation

Francisella tularensis is a Gram-negative bacterium that causes tularemia, a fatal zoonotic disease. F. tularensis has been used in the bioweapon programs of several countries. Its potential use as a bioterrorism agent led the CDC to classify F. tularensis as a Tier 1 Select Agent. The cytosolic sensor absent in melanoma 2 (Aim2) detects double-stranded DNA in the cytosol of infected cells and subsequently assembles a multiprotein complex known as the inflammasome. Inflammasome activation drives the secretion of IL-1{beta} and IL-18, key proinflammatory cytokines required for controlling F. tularensis infection. Prior studies have shown that F. tularensis actively suppresses Aim2 inflammasome activation; however, the underlying mechanism remains unknown. We hypothesized that F. tularensis suppresses Aim2-mediated responses by modulating the intracellular redox environment. We utilized an F. tularensis mutant lacking OxyR ({Delta}oxyR), a transcriptional regulator that controls the expression of major antioxidant enzymes. Our results show that macrophages infected with the {Delta}oxyR mutant exhibit significantly higher levels of Aim2-dependent Caspase-1 and IL-1{beta} than those infected with wild-type bacteria. The expression of interferon regulatory factor 1 and the guanylate-binding proteins GBP2 and GBP5, upstream signaling components of the Aim2 inflammasome, is markedly higher in {Delta}oxyR-infected macrophages than in controls. These changes were absent in {Delta}oxyR-infected NADPH oxidase-deficient macrophages, which are unable to generate reactive oxygen species. Collectively, these findings demonstrate that macrophage redox environment plays a key role in activating signaling components required for Aim2 inflammasome activation. This work advances our understanding of how F. tularensis-encoded factors subvert host innate immune defenses.

immunology↗

bioRxiv2026

Comparative transcriptomic analysis reveals signatures of selection for orb-weaving behavior in spiders

Spiders (Araneae) are responsible for one of the most captivating and intricate examples of animal architecture in the natural world: the web. But only certain groups of spiders weave the familiar spiral-shaped orb web, and the evolutionary origin of orb-weaving has left arachnologists tangled in a debate for the past decade. Since phylogenetic studies rejected the long-held belief that orb-weavers were monophyletic, two competing hypotheses have emerged: that the cribellate (dry) and ecribellate (sticky) orb webs arose independently and convergently, or that the ability to weave the orb originated with web-spinning common ancestors of all extant orb-weavers and was subsequently lost in many non-orb-weaving descendants. Attempts to reconstruct the ancestral state of the orb web have reached conflicting conclusions as a result of disagreements about the species phylogeny and the definition of orb-weaving. As a potential solution to this phylogenetic impasse, we tested orthologous genes from across the genomes of 98 species of spiders for evidence of both convergent positive selection and relaxed selection corresponding to the orb-weaving phenotype, the patterns that we would expect to be caused by each of the competing hypotheses on the origins of the orb. Using a permutation-based approach, we also compared the odds of gene loss and duplication between orb-weavers and non-orb-weaving spiders and identified genes whose copy number differ significantly between the two phenotypic groups. Through these analyses, we integrate the evolutionary history and genetic basis of orb web-associated traits, providing unique insights into the emergence of complex behavior.

evolutionary biology↗

bioRxiv2026

A cortical basis for perception of internal gut sensations

Interoception, the sensing of internal bodily signals, is essential for brain-body interactions and shapes emotion, cognition, and behavior1-5. Subconscious internal signals, including heartbeats or stomach fullness, can rise to conscious awareness, and this process can improve with practice, as seen in meditation, mindful eating, or toilet training in early infancy. Conversely, disrupted interoception is emerging as a common deficit in diverse psychiatric disorders1,3,6,7. Nevertheless, we still lack a fundamental understanding of the neurobiological basis of perception and conscious reporting of internal sensations. Here, we combine genetic and ultra-sensitive optogenetic tools in mice to establish a quantitative framework for studying internal perception. We developed a behavioral task in which mice report detecting non-invasive optogenetic activation of gut mechanosensory neurons, establishing "interoceptive psychophysics". We combine this approach with cellular-resolution imaging and manipulations to reveal the neuronal basis for perception of these internal gut sensations in the interoceptive insular cortex. While representations of sensory stimuli were consistently observed in insular cortex across different tasks, we found that perceptual reports were only encoded during a more difficult psychophysics task, but not during basic detection. Accordingly, manipulation of insular cortex activity affected behavioral reports only in the psychophysics task. These findings reveal a neural basis for perception of internal gut sensations and provide a blueprint for future quantitative exploration of other interoceptive modalities.

neuroscience↗

bioRxiv2026

Engineering the Self-assembly of Bacterial Microcompartment Shell Proteins via Charged Mutations

AbstractProtein self-assembly is a fundamental biological process of great importance for the design and synthesis of biomaterials. Developing the ability to precisely manipulate protein assembly would greatly expand both our understanding of the process and our biotechnological capabilities. Within bacteria, proteins that self-organize to form bacterial microcompartments (MCPs) offer an excellent model system for studying protein self-assembly and advancing biomaterial design capabilities. MCPs consist of irregular polyhedral shells that encase an enzyme core, functioning as enzymatic nanoreactors. In isolation, the abundant shell proteins of the 1,2-propanediol utilization (Pdu) MCP, PduA and PduJ, have a high propensity to self-assemble into tubular structures, analogous in form to carbon nanotubes. Here, we design and characterize tubular structures formed by hexameric PduA and PduJ proteins. We demonstrate that altering hexamer charge offers a systematic strategy for modulating the higherorder assembly of PduA and PduJ across multiple contexts by integrating molecular dynamics simulations with heterologous overexpression, cell-free, and in vivo Salmonella enterica serovar Typhimurium LT2 experiments. First, using molecular simulation, we find that tube chirality and radius play critical roles in determining structural stability and flexibility. Next, overexpression and cell-free experiments show that increasing the overall negative charge of assembling subunits consistently promotes self-assembly into tubular structures. We find that this holds true in the native MCP system, as these same mutations promote the formation of tubular MCP structures in S. enterica LT2. Our results collectively reveal that both electrostatic interactions and fields generated by charges on proteins can be leveraged to control protein-based nanostructures.

biochemistry↗

bioRxiv2026

CRISPR-enabled genetic screens identify synthetic lethal targets across frequently altered cancer drivers

Synthetic lethality (SL) provides a treatment paradigm for targeting cancer with alterations in driver genes that are not conventionally druggable, including loss-of-function (LoF) mutations in tumor suppressor genes and gain-of-function (GoF) alterations in oncogenes. We undertook a series of genome-wide CRISPR screens using functionally validated isogenic cell lines and also conducted a large-scale SL analysis using data from the cancer dependency map (DepMap). We charted SL interactions across 15 genetic alterations characteristic of diseases with high incidence and unmet clinical need: FBXW7, CCNE1, CDK12, ARID1A, KMT2D, DNMT3A, TET2, KEAP1, STK11, IDH1, SF3B1, SRSF2, U2AF1, chromosome 18q loss, and chromosome 13q loss. We show validation of several SL interactions between tractable targets with cancer drivers, including ARID1A and the hexosamine biosynthetic pathway aminotransferase GFPT1, STK11 with CAMK protein kinase family members including MARK2, FBXW7 and the CDK1 regulatory kinase PKMYT1, and CCNE1 amplification and the anaphase promoting complex or cyclosome (APC/C). In summary, this study offers a rich resource of genetic interactions across cancer drivers enabling the discovery of new biological insights and drug targets for future therapeutic development.

cancer biology↗

bioRxiv2026

Focal brain stimulation sites that modify autonomic arousal map to a convergent brain circuit and potential therapeutic target

Causal modulation of autonomic outflow could yield new therapeutic targets for autonomic hyperactivation. We employed three natural experiments in which different brain regions were targeted using transcranial magnetic stimulation (TMS) (n=139 sites, n=14 individuals), deep brain stimulation (n=392 sites, n=58 individuals), or low-intensity focused ultrasound (n=46 sites, n=23 individuals) with subsequent autonomic measurements. Using a human connectome database (n=1000) as a wiring diagram, we identified a convergent brain circuit that, when focally modulated, transiently reduces autonomic arousal. This circuit significantly resembled previously reported causal circuits for posttraumatic stress disorder (PTSD) and anxiety. In independent datasets, TMS to the autonomic arousal circuit reduced laboratory startle in healthy volunteers (n=28), lesions to this circuit reduced exaggerated startle in PTSD (n=193), and TMS to this circuit reduced anxiety-related autonomic symptoms in patients with clinically significant anxiety (n=30). Thus, the convergent circuit may serve as a potential neuromodulation target for autonomic hyperactivation.

neuroscience↗

bioRxiv2025

Acriflavine delivery via Polyurethane nanocapsules to treat neovascular age-related macular degeneration

Choroidal neovascularization is a complication associated with retinal diseases such as age-related macular degeneration (AMD), a leading cause of vision loss in the developed world. Choroidal neovascular membrane (CNVM) refers to the abnormal growth of blood vessels in the retina which results in exudation and/or hemorrhage, leading to photoreceptor damage and vision loss. Currently first-line treatment for CNVM include intravitreal injections of vascular endothelial growth factor (VEGF)-binding antibodies that prevent the growth of these leaky blood vessels. Unfortunately, anti-VEGF drugs often require frequent injections, and prolonged VEGF inhibition has been associated with retinal atrophy and decreased long term effectiveness in some patients. This study presents the use of Acriflavine, a small molecule HIF1 inhibitor loaded polyurethane nanocapsules to treat CNVM in a rat model. Fourteen days following laser injury and intravitreal drug administration, CMVM size was significantly reduced in acriflavine nanocapsule and free acriflavine treated animals as compared to drug free controls. Moreover, acriflavine nanocapsules reduce CNVM incidence compared to drug free controls by approximately 25%. Among the different delivery routes tested, intravitreal delivery of acriflavine nanocapsules was found to be superior to subretinal and suprachoroidal delivery for reducing CNVM area without causing significant damage to the neural retina. This paper presents the synthesis, characterization and the effectiveness of the polyurethane based acriflavine delivery system in treating choroidal neovascularization.

pharmacology and toxicology↗