Biology subjects

Chavez, M.

Publications and source records attributed to Chavez, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Programmable Surface Receptor-Mediated Cell Targeting with Designer Antibody-Routed Nanoparticles (DARTs)

Precise in vivo delivery remains a massive barrier to therapeutic genome editing. Recently, major strides have been made towards cell type-specific delivery, with potential to improve the safety profiles of future gene therapies. However, programming such targeted tropism is limited by the minimal repertoire of scFv sequences, nanobodies, and viral fusogens that enable cell-type specificity, and the slow, iterative design-build-test cycle required to identify and optimize them. Here, we overcome this bottleneck by developing the designer antibody-routed (DART) platform: a modular, plug-and-play tool that decouples delivery vehicle production from tropism engineering. By presenting generic, bioorthogonal antibody-binding interfaces on the surfaces of enveloped particles, the DART system enables conjugation of those particles with off-the-shelf antibodies that direct cell entry without requiring genetic or chemical manipulation. Designer antibody-routed virus-like particles (DARTs) leverage this facile conjugation method to interrogate and identify transduction-competent surface antigens across cell types. They enable combinatorial targeting and the discovery of antigens that synergistically enhance transduction. Finally, DARTs function in the fetal murine nervous system, empirically identifying CD56 as a previously uncharacterized surface antigen enabling editing in hard-to-transduce neural populations. Overall, the DART platform provides a universal tool for rapidly profiling unique, targetable antigens and leveraging them for precision editing applications.

bioengineering↗

bioRxiv2026

Tendon-derived injectable bio-instructive gel augments tenogenic differentiation of iMSC-SCX cells and extracellular matrix remodeling

In the US, 33 million musculoskeletal injuries have been reported per year, with 50% involving tendons and ligaments in both athletic and aging populations. Tendon repair often results in the formation of biomechanically inferior scar tissue rather than functional regeneration. Local cell therapy is garnering significant interest in tendon repair because it provides a targeted means to repopulate defects with potent therapeutic cells. Here, we developed a porcine tendon-derived thermoresponsive extracellular matrix hydrogel (TG) as an injectable, bio-instructive carrier for scleraxis-overexpressing induced mesenchymal stem cell derived tenocytes (iTenocytes), with the goal of improving cell retention and overall transplantation success. TG was compositionally distinct from purified collagen (PC, from rat tail type 1 collagen) and exhibited favorable material properties for a minimally invasive percutaneous strategy, including thermoresponsive gelation, shear-thinning injectability, retention at the injection site, and controlled biodegradation. In vitro, TG supported three-dimensional cell residence, promoted cell interconnectivity and redistribution at the matrix interface, and increased collagen type I release from iTenocytes compared to those embedded in PC. Transcriptomic and proteomic analyses further showed that TG enhanced programs associated with tenogenic maturation, extracellular matrix assembly, focal adhesion, mechano-transduction, and remodeling. In a rat Achilles tendon partial defect model, both optical imaging and histological analyses demonstrated retention of iTenocytes at the injection site. Additionally, confocal imaging demonstrated retention of iTenocytes within the defect site for up to 10 days. Together, these findings identify TG as a biofunctional injectable carrier that supports the tenogenic characteristics of iTenocytes and enhances their local persistence after transplantation.

cell biology↗

bioRxiv2026

Strong effects of soil microbes on early-life defense alter phenotypic correlations in plant leaves

Microbes have wide-ranging effects on host phenotype. However, whether these effects extend to the relationships among host traits remains unknown. We tested whether microbes affect phenotypic correlations among early life traits in the weedy legume Medicago lupulina. In a field common garden, we inoculated plants with two types of microbes: nitrogen-fixing bacteria and rhizosphere microbial communities. We found that microbes modify phenotypic integration (phenotypic correlations) in leaves, primarily due to effects on independent effects on leaflet area and trichome density, a defense trait. While microbial effects on leaflet size were associated with overall plant growth, variation in trichome density was decoupled from growth and not predicted by investment in mutualism. Our results highlight the unique insights that can come from a multivariate approach to organismal plasticity, and raise the intriguing possibility that microbes may have an outsized impact on defense traits and their integration with organismal function.

Plant Biology↗

bioRxiv2026

Modulating Inflammation in Post-Traumatic Osteoarthritis using iPSC-derived Anti-inflammatory Macrophages

Post-traumatic osteoarthritis (PTOA) is a common long-term consequence of joint injury and a major cause of chronic pain and disability, yet no disease-modifying therapies are currently available. A central barrier to effective intervention is the persistence of maladaptive synovial inflammation, driven in part by macrophage-mediated signaling that sustains tissue degeneration and pain. Here, we developed a scalable, chemically defined platform to generate human induced pluripotent stem cell (iPSC)-derived anti-inflammatory macrophages (iMac-M2) as an off-the-shelf cell therapy designed to restore joint immune homeostasis after injury. These cells maintained a stable anti-inflammatory phenotype and function under osteoarthritis-relevant inflammatory conditions and suppressed inflammatory and catabolic responses in human joint cell co-culture systems. In a preclinical model of PTOA, intra-articular delivery of iMac-M2 after injury improved functional and structural outcomes while modulating synovial inflammatory and pain-associated transcriptional programs. Treatment was well tolerated, with no evidence of systemic immune activation or ectopic tissue formation. Together, these findings support iPSC-derived macrophage therapy as a clinically translatable immunomodulatory strategy to interrupt early inflammatory drivers of PTOA and preserve joint health following injury.

cell biology↗

bioRxiv2026

Brain-heart interactions predict brain activity recovery after systemic anoxia

Global cerebral anoxia is a leading cause of death and resuscitated patients often remain persistently affected by neurological deficits. While previous studies suggest that brain-heart electrophysiological interactions may predict severity and prognosis after hypoxic brain injury coma, little is known about the brain-heart dynamics at near-death. Gaining insight into these mechanisms is crucial for developing targeted interventions in critical conditions. Using a rodent model of reversible systemic anoxia (n=29, male and female rats), we investigated whether brain-heart interactions during the asphyxia onset could predict the return of brain electrical activities after resuscitation. Electrophysiological recordings confirmed that cerebral activity declines following asphyxia, coinciding with increased heart rate variability. Notably, the strong coupling between cardiac parasympathetic activity and high-frequency brain activity in the somatosensory cortex and hippocampus serves as a key predictor of a survival. Our study underscores the potential involvement of the brain-heart axis in the physiology of dying and the potential prognostic significance of the underlying mechanisms, paving the way for translational research into critical care, based on new characterizations of cardiac reflexes and brain-heart interactions. Significance StatementUnderstanding the physiological processes that determine survival and recovery following systemic anoxia is critical for improving outcomes in critical care. This study reveals that brain-heart dynamics during the onset of systemic anoxia relate to survival after resuscitation. In particular, the coupling between parasympathetic cardiac activity and high-frequency brain signals. Using a reversible anoxia rodent model, we demonstrate that early brain-heart interactions are not merely consequences of anoxia, but active markers of resilience. These findings offer a novel framework for understanding the physiology of dying and to ultimately developing prognostic tools based on real-time physiological monitoring.

neuroscience↗

bioRxiv2026

Artificial sediments enable reproducible cultivation and recapitulate ecological interactions of cable bacteria

Cable bacteria are filamentous microbes that couple sulfide oxidation to oxygen reduction over centimeter distances via long-distance electron transport. While their activity creates characteristic biogeochemical gradients that shape sediment ecology, the study of cable bacteria has been constrained by the chemical and physical heterogeneity of the natural sediments they inhabit. To date, laboratory cultivation efforts have relied on these undefined environmental matrices. Here, we established a reproducible enrichment and cultivation platform using an artificial sediment matrix coupled with chemically defined media. This matrix successfully supported the growth of both freshwater and marine cable bacteria and enabled serial propagation over multiple transfers. Microsensor profiling confirmed that the incubations recapitulated hallmark geochemical signatures, including the sulfide, oxygen and pH gradients associated with electrogenic sulfur oxidation. Scanning electron microscopy confirmed the presence of cable bacteria, while 16S rRNA sequencing confirmed enrichment of the cable bacteria together with a stable co-enriched community that included taxa associated with sulfur and iron cycling as well as cellulose decomposition. This defined cultivation system eliminates the variability inherent to natural samples, providing a controlled platform for dissecting the physiology, genetics, and microbial interactions of cable bacteria.

microbiology↗

bioRxiv2026

Circulating biomarkers in serum from aortic valve stenosis patients predict sex-specific drug responses in valve myofibroblasts

Aortic valve stenosis (AVS) is a prevalent, sexually dimorphic cardiovascular disease characterized by fibro-calcification of the aortic valve leaflet. Sex differences in AVS arise in part from sexually dimorphic serum composition that differentially regulate valvular interstitial cell (VIC) myofibroblast activation. However, how individual serum factors contribute to sex-specific drug responses targeting VIC myofibroblast activation remains unknown. Here, we integrate serum proteomic profiling with in vitro drug screening using hydrogel biomaterials to identify sex-specific regulators of antifibrotic drug efficacy. We found that Insulin-like Growth Factor Binding Protein 2 (IGFBP2) serum levels are associated with resistance to the antifibrotic drug Evogliptin only in female VICs cultured with female AVS serum. This mechanism is driven by IGFBP2-mediated activation of Rho/ROCK and focal adhesion kinase signaling pathways that counteract Evogliptin treatment. Our findings reveal a sex-specific, serum-mediated mechanism of Evogliptin resistance and highlight IGFBP2 as a candidate biomarker for stratifying female AVS patients for Evogliptin treatment. More broadly, these findings underscore the importance of incorporating sex-stratified biomarker analyses into AVS therapeutic development to improve patient-specific treatment recommendations.

bioengineering↗

bioRxiv2025

A Porcine Model of Intervertebral Disc Injury Recapitulates Human Discogenic Pain via Notochordal Cell Loss and Pain-inducing Nucleus Pulposus Cell Emergence

Lower back pain (LBP) is one of the most common causes of disability, with up to 40% of LBP cases attributed to intervertebral disc (IVD) degeneration. While small animal models are widely used to study IVD and LBP, the small size of their IVDs limits translational and biological relevance. Large animal models more accurately emulate human disease; however, methods of measuring LBP are not well established. Pigs were also considered unfit for LBP research, due to notochordal cells (NCs) persistence through life, unlike humans. We developed a comprehensive porcine model with quantitative measure of discogenic pain via biobehavioral testing (BBT), MRI, and multi-omics tissue analysis of IVD and DRGs. MRI demonstrated the progression of IVD degeneration beginning at 4 weeks post-injury. BBTs showed the development of significant pain responses by week 4 post-injury, supported by transcriptomics of injury matched DRGs. Single cell transcriptomics, trajectory and cell-cell communication analyses suggest that, with injury, NCs are differentiating to nucleus pulposus cells (NPCs). Furthermore, NPCs showed upregulation of cellular stress, neural outgrowth, and inflammation pathway, consistent with pain-inducing distress signals found in human samples. This study establishes novel MRI and BBT-based methods for quantifying LBP in pigs and supports its translational relevance to human discogenic LBP. The identification of LBP-associated clusters mirrors our previous finding in humans. Moreover, the shift of NC to NPC phenotype further supports that the porcine model is relevant to human pathology, as the injury induced accelerated aging and loss of NCs with IVD degeneration and discogenic pain.

developmental biology↗

bioRxiv2025

Imagined movement increases the segregation of brain-heart networks

Understanding the mechanisms of motor imagery, the mental simulation of movement without execution, is key for the development of neurotechnologies, including understanding inter-individual variability in motor imagery performance. For instance, for detecting covert motor intent in noncommunicative patients or refining motor commands through brain-computer interfaces. While motor imagery engages motor-related brain regions, its precise mechanisms remain unclear, particularly in relation to cardiac dynamics. Evidence suggests heart-rate variability features have potential to enhance tasks classifications, yet the brain-heart relationship is not well understood. In this study, we examined motor imagery learning using a task involving right-hand grasping imagery. We found that motor imagery is correlated with a task-dependent modulation of cardiac sympathetic activity and its relation with directed functional connectivity from the supplementary motor area to premotor and primary motor cortices. Additionally, cerebellar-supplementary motor area segregation, in relation to cardiac parasympathetic activity, indexed longitudinal motor learning. These results suggest that dynamic reconfiguration of brain-heart interactions contributes to sensorimotor function and learning-related physiology during motor imagery, supporting the brain-heart axis as a functional component of motor imagery rather than a passive correlate.

neuroscience↗

bioRxiv2025

Cardiac-neurovascular crosstalk: Cardiac rhythms reveal maladaptive cerebral autoregulation and constrained ventilatory status

In brain-heart interactions, several pathways have been proposed to mediate feedback loops between systems. Among these, cerebrovascular dynamics operate at their interface. However, how cardiovascular control, ventilation mechanisms, and cerebral autoregulation interact is not well characterized, especially in ageing and post-stroke conditions, where perfusion can be compromised. In a cohort of 57 elderly participants, including 30 stroke survivors, we investigated the relationship between cardiac sympathetic activity and both, cerebral blood flow regulation and ventilatory status. Sympathetic reflexes, assessed via cardiac sympathetic index (CSI) during sit-to-stand transitions, were preserved across all participants, with marginal group differences between stroke and non-stroke populations. However, among individuals with constrained ventilation, indexed by reduced end-tidal CO2 at baseline, we identified a more elevated CSI following postural change, scaling with the degree of CO2 dysregulation. Furthermore, transcranial Doppler measurements revealed exaggerated changes in mean flow velocity (MFV) within the right middle cerebral artery in most participants. These MFV shifts significantly correlated with the magnitude of cardiac sympathetic change under orthostatic stress, suggesting that CSI can capture maladaptive cerebrovascular responses. Together, these findings highlight a distinct cardiac-cerebrovascular crosstalk in elderly individuals, revealing patterns consistent with compensatory or maladaptive sympathetic overactivation under conditions of impaired cerebrovascular control.

neuroscience↗

bioRxiv2025

Neuronal avalanches as a predictive biomarker of BCI performance- towards a tool to guide tailored training

Motor imagery-based Brain-Computer Interfaces (BCIs) restore control in persons with motor impairments, but up to 30% of users struggle--a phenomenon known as "BCI inefficiency". This study tackles a key limitation of current protocol: the use of fixed-length sessions training paradigms that ignore individual learning variability. We propose a novel approach based on neuronal avalanches-- spatiotemporal cascades of brain activities--as biomarkers to characterize and predict user-specific learning. From electroencephalography data across four sessions in 20 subjects, we characterized avalanches by their length and their spatiotemporal size. These features showed significant training and task effects and were found to correlate to BCI performance across sessions. We further assessed their ability to predict BCI success through longitudinal models, achieving up to 91% accuracy, improved by spatial filtering on selected brain regions. These findings demonstrate the utility of neuronal avalanche dynamics as robust biomarkers for BCI training, supporting the development of personalized protocols aimed at mitigating BCI illiteracy.

neuroscience↗

bioRxiv2024

Determining sex differences in drug combinations targeting aortic valve myofibroblast activation using an artificial intelligence derived platform

Aortic valve stenosis (AVS) is a sexually dimorphic disease where aortic valve leaflets develop fibrosis and calcification, leading to heart failure if untreated. Sex differences in AVS progression depend on valvular interstitial cells (VICs) activating to myofibroblasts that drive aberrant extracellular matrix remodeling. To date, no treatment strategies have leveraged cellular sex differences to determine drug combinations that effectively target VIC myofibroblast activation. Here, we harnessed IDentif.AI, an artificial intelligence (AI)-derived drug optimization platform, to optimize sex-specific synergistic drug combinations that may prevent and reverse VIC myofibroblast activation on hydrogel biomaterials. The results reveal that anti-fibrotic drug efficacy and combinatorial interactions are dependent on cell sex. This study provides a framework for developing clinically relevant AVS treatment strategies through the integration of high-throughput hydrogel cell culture platforms and AI-driven drug optimization. The workflow towards designing targeted AVS drug combinations may help accelerate AVS drug development for male and female patients and address health disparities in AVS treatment outcomes.

bioengineering↗

bioRxiv2024

The human ciliopathy protein RSG1 links the CPLANE complex to transition zone architecture

Cilia are essential organelles and variants in genes governing ciliary function result in ciliopathic diseases. The Ciliogenesis and PLANar polarity Effectors (CPLANE) protein complex is essential for ciliogenesis in animals models but remains poorly defined. Notably, all but one subunit of the CPLANE complex have been implicated in human ciliopathy. Here, we identify three families in which variants in the remaining CPLANE subunit CPLANE2/RSG1 also cause ciliopathy. These patients display cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. We further show that these alleles disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins. Moreover, APMS reveals that Rsg1 binds the CPLANE and also the transition zone protein Fam92 in a GTP-dependent manner. Finally, we show that CPLANE is generally required for normal transition zone architecture. Our work demonstrates that CPLANE2/RSG1 is a causative gene for human ciliopathy and also sheds new light on the mechanisms of ciliary transition zone assembly.

cell biology↗

bioRxiv2024

Measuring the time-dependent effects of dobutamine on the modulations of cardiac activity in rats

Assessing cardiac dynamics over time is essential for understanding cardiovascular health and its parallel patterns of activity with the brain. We present a methodology to estimate the time-resolved sympathetic and parasympathetic modulations of cardiac dynamics, specifically tailored for the rat heart. To evaluate the performance of our method, we study a dataset comprising spontaneously hypertensive rats and Wistar-Kyoto rats. These rats were administered dobutamine to elicit autonomic dynamics. The results obtained from our method demonstrated accurate time-resolved depiction of sympathetic reactivity induced by dobutamine administration. These responses closely resembled the expected autonomic alterations observed during physical exercise conditions, albeit emulated pharmacologically. We further compared our method with standard measures of low-frequency (LF) and high-frequency (HF) components, which are commonly used, although debated, for sympathetic and parasympathetic activity estimation. The comparisons with LF and HF measures further confirmed the effectiveness of our method in better capturing autonomic changes in rat cardiac dynamics. Our findings highlight the potential of our adapted method for time-resolved analysis in future clinical and translational studies involving rodents models. The validation of our approach in animal models opens new avenues for investigating the relationship between ongoing changes in cardiac activity and parallel changes in brain dynamics. Such investigations are crucial for advancing our understanding of the brain-heart connection, particularly in cases involving neurodegeneration, brain injuries, and cardiovascular conditions. Key points- We developed a method for time-resolved estimation of sympathetic and parasympathetic modulations in rat cardiac dynamics, validated against standard LF and HF measures. - We used a cohort of spontaneously hypertensive rats and Wistar-Kyoto rats, with dobutamine administration to induce autonomic responses. - Our method accurately depicted time-resolved sympathetic reactivity similar to autonomic changes during physical exercise. - Our findings suggest potential for future clinical and translational studies on the brain-heart connection, particularly in cardiovascular conditions.

neuroscience↗

bioRxiv2024

Cycle-frequency content EEG analysis improves the assessment of respiratory-related cortical activity

Time-Frequency (T-F) analysis of EEG is a common technique to characterise spectral changes in neural activity. This study explores the limitations of utilizing conventional spectral techniques in examining cyclic event-related cortical activities due to challenges, including high inter-trial variability. Introducing the Cycle-Frequency (C-F) analysis, we aim to enhance the evaluation of cycle-locked respiratory events. For synthetic EEG that mimicked cycle-locked pre-motor activity, C-F had more accurate frequency and time localization compared to conventional T-F analysis, even for a significantly reduced number of trials and a variability of breathing rhythm. Preliminary validations using real EEG data during both unloaded breathing and loaded breathing (that evokes pre-motor activity) suggest potential benefits of using the C-F method, particularly in normalizing time units to cyclic activity phases and refining baseline placement and duration. The proposed approach could provide new insights for the study of rhythmic neural activities, complementing T-F analysis.

neuroscience↗

bioRxiv2023

Robust and time-resolved estimation of cardiac sympathetic and parasympathetic indices

The time-resolved analysis of heart rate (HR) and heart rate variability (HRV) is crucial for the evaluation of the dynamic changes of autonomic activity under different clinical and behavioral conditions. Standard HRV analysis is performed in the frequency domain because the sympathetic activations tend to increase low-frequency HRV oscillations, while the parasympathetic ones increase high-frequency HRV oscillations. However, a strict separation of HRV in frequency bands may cause biased estimations, especially in the low frequency range. To overcome this limitation, we propose a robust estimator that combines HR and HRV dynamics, based on the correlation of the Poincare plot descriptors of interbeat intervals from the electrocardiogram. To validate our method, we used electrocardiograms gathered from open databases where standardized paradigms were applied to elicit changes in autonomic activity. Our proposal outperforms the standard spectral approach for the estimation of low- and high-frequency fluctuations in HRV, and its performance is comparable to newer methods. Our method constitutes a valuable, robust, time-resolved, and cost-effective tool for a better understanding of autonomic activity through HR and HRV in healthy state and potentially for pathological conditions.

neuroscience↗

bioRxiv2023

Single Cell Transcriptomics-informed Induced Pluripotent Stem Cells Differentiation to Tenogenic Lineage

During vertebrate embryogenesis, axial tendons develop from the paraxial mesoderm and differentiate through specific developmental stages to reach the syndetome stage. While the main roles of signaling pathways in the earlier stages of the differentiation have been well established, pathway nuances in syndetome specification from the sclerotome stage have yet to be explored. Here, we show stepwise differentiation of human iPSCs to the syndetome stage using chemically defined media and small molecules that were modified based on single cell RNA-sequencing and pathway analysis. We identified a significant population of branching off-target cells differentiating towards a neural phenotype overexpressing Wnt. Further transcriptomics post-addition of a WNT inhibitor at the somite stage and onwards revealed not only total removal of the neural off-target cells, but also increased syndetome induction efficiency. Fine-tuning tendon differentiation in vitro is essential to address the current challenges in developing a successful cell-based tendon therapy.

developmental biology↗

bioRxiv2023

Programmable Drug Control of Receptor Valency Modulates the Potency of Cell Therapeutics

Designer T cells offer a novel paradigm for treating diseases like cancer, yet they are often hindered by target recognition evasion and limited in vivo control. To overcome these challenges, we develop valency-controlled receptors (VCRs), a novel class of synthetic receptors engineered to enable precise modulation of immune cell activity. VCRs use custom-designed valency-control ligands (VCLs) to modulate T cell signaling via spatial molecular clustering. Using multivalent DNA origami as VCL, we first establish that valency is important for tuning the activity of CD3-mediated immune activation. We then generate multivalent formats of clinically relevant drugs as VCL and incorporate VCR into the architecture of chimeric antigen receptors (CARs). Our data demonstrate that VCL-mediated VCRs can significantly amplify CAR activities and improve suboptimal CARs. Finally, through medicinal chemistry, we synthesize programmable, bioavailable VCL drugs that potentiate targeted immune response against low-antigen tumors both in vitro and in vivo. Our findings establish receptor valency as a core mechanism for enhancing CAR functionality and offer a synthetic chemical biology platform for strengthening customizable, potent, and safer cell therapies.

synthetic biology↗