Biology subjects

Schwartz, A.

Publications and source records attributed to Schwartz, A..

15 recordsLinked to original sources

bioRxiv2026

CytosMPS: an automated multimodal pooled screening platform for protein, morphology and transcriptomics

Cytos Multimodal Pooled Screening (CytosMPS) measures CRISPR guide identity, morphology, native 3' transcriptome, and protein abundance and localization in the same fixed cells. Following IL-1{beta} stimulation, cells with higher nuclear NF-{kappa}B show lower phospho-p38/HSP27 and higher NFKBIA/DUSP1 in the same cell, a measurement neither imaging nor transcriptomics alone provides. TGFBR2 and CTNNB1 perturbations produce distinct multimodal phenotypes. Guide representation and perturbation transcriptional responses agree with an orthogonal single-cell transcriptomic platform.

cell biology↗

bioRxiv2026

A double-blinded, placebo-controlled field trial of an OspA-based oral reservoir targeted vaccine against Borrelia burgdorferi

Lyme disease, caused by Borrelia burgdorferi and transmitted by Ixodes scapularis ticks, remains a significant vector-borne illness in the United States. Small mammal reservoirs, particularly Peromyscus leucopus, play a critical role in B. burgdorferi maintenance. Here we conducted a five-year, randomized, double-blinded, placebo-controlled field trial deploying an oral OspA-based reservoir targeted vaccine (RTV) across seven Maryland sites. Bayesian modeling provided estimates of vaccine impact on mouse anti-OspA antibody levels, nymphal tick infection prevalence (NIP), mouse infection rates, and seroconversion to B. burgdorferi in hunting dogs. RTV sites exhibited an estimated 10.5% proportional increase in protective murine anti-OspA antibody levels and a 15.4% reduction in NIP by year five. We also found a lower infection prevalence in mouse blood fed nymphal ticks (9.8%). RTV sites exhibited modest decreases in mouse infection prevalence and dog seroconversion rates were similar between groups. Our results indicate that anti-OspA antibody in vaccinated-infected P. leucopus reduced B. burgdorferi summertime larval infection prevalence, measured as NIP reductions the following spring. This suggests that OspA-based oral RTV reduces B. burgdorferi transstadial transmission within tick populations. Our findings advance development of reservoir targeted solutions for Lyme disease prevention. Further evaluation of impacts on incidental hosts is needed.

microbiology↗

bioRxiv2025

The neural correlates of novel versus familiar metaphors in healthy young adults: A functional near-infrared spectroscopy study

Despite extensive investigation, the neural correlates of metaphor processing remain debated. Poor theoretical and experimental control of variables that drive metaphor activation-- particularly the constructs of novelty and familiarity--may be the reason for past discrepancies between studies. To address this issue, we used functional near-infrared spectroscopy (fNIRS) and a carefully designed paradigm modified from Cardillo et al. (2012) to investigate how neural activation varies by sentence type (metaphorical versus literal sentences) and novelty (completely novel versus familiarized phrases). Activity was significantly greater for metaphorical over literal sentences in the left inferior frontal gyrus, pars triangularis (LIFGtri), left inferior parietal cortex, right IFG, pars opercularis (RIFGop), and right angular gyrus (RAG). Novel metaphors to which participants had no prior exposure had significantly higher (albeit weak) effects within RIFGop, RAG, and right middle temporal gyrus (RMTG) compared to novel metaphors to which participants were exposed just prior to the fNIRS experiment. Pre-exposed, more familiar metaphors significantly activated a wider network of regions compared to novel metaphors, including bilateral middle frontal gyrus (MFG), bilateral IFGtri, and LMTG. A greater response time difference between conditions was associated with less LMFG activity for metaphors over literal sentences but higher LMTG activity for novel over more familiar metaphors. Taken together, these findings suggest that metaphors--particularly novel metaphors--do engage right hemisphere cortex more than other phrase types (literal sentences, more familiar metaphors) but that the effects are weaker than condition differences within canonical left language network and domain-general multiple demand network regions.

neuroscience↗

bioRxiv2025

B cells specific for polyomavirus-derived oncoprotein are predictive of Merkel cell carcinoma progression

Merkel cell carcinomas typically arise from clonal integration of the Merkel cell polyomavirus. Immunogenic viral oncoproteins then lead to tumorigenesis. Oncoprotein-specific T cells are essential for anti-MCC immunity, but it is unclear whether B cells promote tumor control. Here, we analyzed the frequency and phenotype of viral oncoprotein-specific and total B cells in 47 blood samples and 19 unmatched tumors from MCC patients-- of which 8 out 19 progressed. The phenotype of blood B cells did not correlate with MCC patient outcomes. In contrast, all 11 patients with robust oncoprotein-specific antibody-secreting and/or germinal center B cells in tumors experienced long-term MCC control. In vitro, B cells engineered to be specific for viral oncoproteins increased the sensitivity of oncoprotein-specific CD4+ T cells by over 50-fold. Together, our findings suggest that cancer-specific B cells promote anti-tumor immunity via increased T cell responses and that cancer-specific B cell augmentation could be therapeutically relevant. Statement of SignificanceThe link between cancer-specific B cells in anti-tumor immunity and clinical outcomes remains poorly defined. Here, we show that tumor-associated B cells specific for a viral oncoprotein expressed in MCC patient tumors predict disease control with remarkable accuracy, establishing their potential as active participants in tumor immunity.

immunology↗

bioRxiv2025

Tuning of Task-Relevant Stiffness in Multiple Directions

The dynamics of any mechanical system can be described in terms of forces and motions. The interaction of these terms is often captured in the metric of mechanical impedance - a generalization of stiffness - used to describe how a mechanical system resists the application of force. The ability to adaptively change impedance is advantageous when encountering variable environmental conditions. Changing impedance in robotic systems is limited, whereas humans can rapidly and elegantly adapt the impedance of their limbs, especially during initial contact with objects. This is especially true for movements of our arms and hands. Multiple studies have examined the arms response to perturbation with the idea of impedance as a reactive component. In this study, we investigate the ability of humans to predictively set their arm impedance in a contact breaking task to perform fast movements to target positions in different directions. Our findings show that subjects (n=20) predictively co-activate antagonist muscles to primarily adjust one component of the arms impedance - stiffness - to match different task constraints before the movement begins irrespective of movement direction. Interestingly, the subjects performance was limited by the task-dependent stiffness rather than the required force and they tended to generate minimal stiffness to perform the task. With this robust strategy, task success is optimized at the expense of energy efficiency. This type of control is essential for the uniquely human ability to interact with objects.

neuroscience↗

bioRxiv2024

Upregulating ANKHD1 in PS19 mice reduces Tau phosphorylation and mitigates Tau-toxicity-induced cognitive deficits

Abnormal accumulation of Tau protein in the brain disrupts normal cellular function and leads to neuronal death linked with many neurodegenerative disorders such as Alzheimers disease. An attractive approach to mitigate Tau-induced neurodegeneration is to enhance the clearance of toxic Tau aggregates. We previously showed that upregulation of the fly gene mask protects against FUS- and Tau-induced photoreceptor degeneration in fly disease models. Here we have generated a transgenic mouse line carrying Cre-inducible ANKHD1, the mouse homolog of mask, to determine whether the protective role of mask is conserved from flies to mammals. Utilizing the TauP301S-PS19 mouse model for Tau-related dementia, we observed that ANKHD1 significantly reduced hyperphosphorylated human Tau in 6-month-old mice. Additionally, there was a notable trend towards reduced gliosis levels in these mice, suggesting a protective role of ANKHD1 against TauP301S-linked degeneration. Further analysis of 9-month- old mice revealed a similar trend of effects. Moreover, we found that ANKHD1 also suppresses the cognitive defect of 9-month-old PS19 female mice in novel object recognition (NOR) behavioral assay. Unlike previous therapeutic strategies that primarily focus on inhibiting Tau phosphorylation or directly clearing aggregates, this study highlights the novel role of ANKHD1 in promoting autophagy as a means to mitigate Tau pathology. This novel mechanism not only underscores ANKHD1s potential as a unique therapeutic target for tauopathies but also provides new insights into autophagy-based interventions for neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Amniotic Fluid Organoids As Personalized Tools For Real-Time Modeling Of The Developing Fetus

Despite biomedical advances, major knowledge gaps regarding human development remain, and many developmental disorders lack effective treatment, representing a huge clinical burden. This results from fetuses being largely inaccessible for analysis. Here, we employ fetal cells in human amniotic fluid (AF) to establish personalized fetal kidney and lung organoids (AFKO and AFLO, respectively), recapitulating fetal organs at single-cell resolution. AFKO harbor key fetal kidney cell populations, including nephrogenic, urothelial and stromal, endocytose albumin, and model PAX2-related anomalies. Strikingly, upon injection into the nephrogenic cortex of human fetal kidney explants, AFKO-derived progenitors integrate into the host progenitor niche and contribute to developing nephrons. AFLO comprise alveolar cells and most airway cell types in a typical pseudostratified structure, upregulate surfactant expression upon corticosteroid treatment, and show functional CFTR channels. Overall, this platform represents a new personalized tool that can be applied to virtually any fetus in real-time, affording unprecedented options in studying development, uncovering mechanisms of in utero pathologies (e.g., congenital anomalies, infections or chemical teratogens) deciphering the developmental origins of chronic diseases, and tailoring treatments for these pathologies, as well as for prematurity-related complications. Importantly, since AF contains cells from additional tissues (e.g., skin and gastrointestinal tract), and is derived in a procedure already performed in many patients, this platform may well become a broadly applicable tool in fetal medicine.

developmental biology↗

bioRxiv2022

Antibody optimization enabled by artificial intelligence predictions of binding affinity and naturalness

Traditional antibody optimization approaches involve screening a small subset of the available sequence space, often resulting in drug candidates with suboptimal binding affinity, developability or immunogenicity. Based on two distinct antibodies, we demonstrate that deep contextual language models trained on high-throughput affinity data can quantitatively predict binding of unseen antibody sequence variants. These variants span a KD range of three orders of magnitude over a large mutational space. Our models reveal strong epistatic effects, which highlight the need for intelligent screening approaches. In addition, we introduce the modeling of "naturalness", a metric that scores antibody variants for similarity to natural immunoglobulins. We show that naturalness is associated with measures of drug developability and immunogenicity, and that it can be optimized alongside binding affinity using a genetic algorithm. This approach promises to accelerate and improve antibody engineering, and may increase the success rate in developing novel antibody and related drug candidates.

bioinformatics↗

bioRxiv2022

Post-transcriptional regulation by copper with a new upstream Open Reading Frame

Copper is essential to most living beings but also toxic. Bacteria have thus developed homeostatic mechanisms to tightly control its intracellular concentration. The 3-gene operon bp2923-bfrG-bp2921 is down-regulated by copper and notably encodes a TonB-dependent transporter in Bordetella pertussis. We show that the protein encoded by bp2923, which is a member of the DUF2946 family, represents a new type of upstream Open Reading Frame (uORF) involved in post-transcriptional regulation of the downstream genes. In the absence of copper, the entire operon is transcribed and translated. Perception of copper by the nascent bp2923-coded protein via its conserved CXXC motif triggers Rho-dependent transcription termination between the first and second genes by relieving translation arrest on a conserved C-terminal RAPP motif. Homologues of bp2923 are widespread in bacterial genomes, where they head operons predicted to participate in copper homeostasis. This work has unveiled an original mode of genetic regulation by a transition metal and identified a regulatory function for a member of an uncharacterized family of bacterial proteins that we have named CruR, for copper-responsive upstream regulator.

microbiology↗

bioRxiv2021

Affinity sedimentation and magnetic separation with plant-made immunosorbent nanoparticles for therapeutic protein purification

The virus-based immunosorbent nanoparticle is a nascent technology being developed to serve as a simple and efficacious agent in biosensing and therapeutic antibody purification. There has been particular emphasis on the use of plant virions as immunosorbent nanoparticle chassis for their diverse morphologies and accessible, high yield manufacturing via crop cultivation. To date, studies in this area have focused on proof-of-concept immunosorbent functionality in biosensing and purification contexts. Here we consolidate a previously reported pro-vector system into a single Agrobacterium tumefaciens vector to investigate and expand the utility of virus-based immunosorbent nanoparticle technology for therapeutic protein purification. We demonstrate the use of this technology for Fc-fusion protein purification, characterize key nanomaterial properties including binding capacity, stability, reusability, and particle integrity, and present an optimized processing scheme with reduced complexity and increased purity. Furthermore, we present a coupling of virus-based immunosorbent nanoparticles with magnetic particles as a strategy to overcome limitations of the immunosorbent nanoparticle sedimentation-based affinity capture methodology. We report magnetic separation results which exceed the binding capacity of current industry standards by an order of magnitude.

bioengineering↗

bioRxiv2020

Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep in db/db mice

Obesity can lead to recurrent upper airway obstruction (obstructive sleep apnea, OSA) during sleep as well as alveolar hypoventilation. We have previously shown that leptin stimulates breathing and treats OSA in leptin-deficient ob/ob mice and leptin-resistant diet-induced obese mice. Our previous data also suggest that leptins respiratory effects may occur in the dorsomedial hypothalamus (DMH). We selectively expressed leptin receptor LepRb in the DMH neurons of obese LepRb-deficient db/db mice (LepRb-DMH mice), which hypoventilate at baseline, and showed that intracerebroventricular injection of leptin in these animals increased inspiratory flow, tidal volume and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in LepRb-DMH animals. We conclude that leptin stimulates breathing and treats obesity related hypoventilation acting on LepRb-positive neurons in the DMH.

physiology↗

bioRxiv2019

Tumor cell-organized fibronectin is required to maintain a dormant breast cancer population

Tumors can undergo long periods of dormancy, with cancer cells entering a largely quiescent, non-proliferative state before reactivation and outgrowth. For a patient, these post-remission tumors are often drug resistant and highly aggressive, resulting in poor prognosis. To understand the role of the extracellular matrix (ECM) in regulating tumor dormancy, we created an in vitro cell culture system that combines carefully controlled ECM substrates with nutrient deprivation to observe entrance into and exit from dormancy with live imaging. We saw that cell populations capable of surviving entrance into long-term dormancy were heterogeneous, containing quiescent, cell cycle arrested, and actively proliferating cells. Cell populations that endured extended periods of serum-deprivation-induced dormancy formed an organized, fibrillar fibronectin matrix via v{beta}3 and 5{beta}1 integrin adhesion, ROCK-generated tension, and TGF{beta}2 stimulation. We surmised that the fibronectin matrix was primarily a mediator of cell survival, not proliferation, during the serum-deprivation stress, bacause cancer cell outgrowth after dormancy required MMP-2-mediated fibronectin degradation. Given the difficulty of animal models in observing entrance and exit from dormancy in real-time, we propose this approach as a new, in vitro method to study factors important in regulating dormancy, and we used it here to elucidate a role for fibronectin deposition and MMP activation.

cancer biology↗

bioRxiv2018

Expression of a recombinant, 4’-Phosphopantetheinylated, active M. tuberculosis Fatty acid Synthase I in E. coli

Fatty acid synthase 1 (FAS I) from Mycobacterium. tuberculosis (Mtb) is an essential protein and a promising drug target. FAS I is a multi-functional, multi-domain protein that is organized as a large (1.9 MDa) homohexameric complex. Acyl intermediates produced during fatty acid elongation are attached covalently to an acyl carrier protein (ACP) domain. This domain is activated by the transfer of a 4-Phosphopantetheine (4-PP, also termed P-pant) group from CoA to ACP catalyzed by a 4-PP transferase, termed acyl carrier protein synthase (AcpS). In order to obtain an activated FAS I in E. coli, we transformed E. coli with tagged Mtb fas1 and acpS genes encoded by a separate plasmid.\n\nWe induced the expression of Mtb FAS I following induction of AcpS expression. FAS I was purified by Strep-Tactin affinity chromatography. Activation of Mtb FAS I was confirmed by the identification of a bound P-pant group on serine at position 1808 by mass spectrometry. The purified FAS I displayed biochemical activity shown by spectrophotometric analysis of NADPH oxidation and by CoA production, using the Ellman reaction. The purified Mtb FAS I forms a hexameric complex shown by negative staining and cryo-EM. Purified hexameric and active Mtb FAS I is required for binding and drug inhibition studies and for structurefunction analysis of this enzyme. This relatively simple and short procedure for Mtb FAS I production should facilitate studies of this enzyme.

microbiology↗

bioRxiv2018

Long-term acclimation to different stress types: revealing tradeoffs between mesophyll and stomatal conductance

Ziziphus spina-christi, a thermophilic tree, became more abundant in the Mediterranean, presumably due to increased winter temperatures. In order to predict the plant acclimation to future climate changes, we attempted to understand which factors underlie photosynthetic stress acclimation.\n\nStress acclimation to three major long-term abiotic stresses (drought, salinity and temperature) was investigated by measuring growth, gas exchange, chlorophyll fluorescence and leaf structure. We developed a stress index that allowed to precisely define stress level, enabling a comparison between stress types. For each stress, photosynthesis-limiting factors were compared: stomatal conductance (gs), mesophyll conductance (gm) and maximum capacity for Rubisco carboxylation (Vcmax).\n\nPhotosynthesis under all stresses was limited mostly by gs and gm (80-90%); whereas biochemistry (Vcmax) made a minor contribution (10-20%). The relative contribution of gs and gm on photosynthetic limitation was influenced by stress type. During acclimation to drought or salinity, photosynthesis was limited by a decline in gs, while intolerance to low temperatures was driven by decline in gm. Low mesophyll-imposed limitation was the best predictor of abiotic stress tolerance.\n\nThe results demonstrate how warming climate benefits thermophilic species. Moreover, current work gives methodology for stress studies, and defines the main factors underlying the plant response to climate change.\n\nHighlightWe have compared the photosynthesis limitation resulting from long-term acclimation to three major a-biotic stresses (drought, salinity and temperature) to understand which limiting-factor are dominant under each type of stress.

plant biology↗

bioRxiv2018

Water availability dynamics have long-term effects on mature stem structure in Vitis vinifera

Vitis vinifera is a climbing vine with wide vessels and high hydraulic conductivity. There is a lack of data on the anatomical structure of the mature vine stem, and most current knowledge is based on first-year shoots. Moreover, the effect of drought stress on anatomical structure has been partly reported in shoots of Vitis vinifera but not in stems.\n\nIn current study two irrigation approaches were applied on Vitis vinifera Merlot vines: constant (low, medium and high irrigation) and dynamic (early/late season water deficit). The following parameters were measured: trunk diameter, annual ring width and area, vessel diameter, specific hydraulic conductivity and stem water potential.\n\nHigh water availability early in the season (high irrigation and late deficit) resulted in vigorous vegetative growth (greater trunk diameter, ring width and area), wider vessels and increased specific hydraulic conductivity. The distribution of large xylem vessels was altered by drought stress, where high water availability early in the season caused a shift of the vessel population towards the wider frequency classes. Interestingly, the early deficit vines showed more negative water potential values late in the season compared to the low irrigation vines. This may imply an effect of anatomical structure on vine water status.\n\nHighlightsWater availability early in the season determines vegetative growth and stem anatomical structure in mature Vitis vinifera vines.

plant biology↗