Biology subjects

Jacques, J.

Publications and source records attributed to Jacques, J..

13 recordsLinked to original sources

bioRxiv2026

Identification of TM4SF1 as a novel tumor-associated antigen in biliary tract cancers targetable by CAR-T cell therapy

Background & Aims: Biliary tract cancers (BTCs) are a rare set of genetically heterogenous and aggressive malignancies associated with delayed presentation and poor prognosis. Thus, there is an unmet clinical need for the development of novel therapeutic strategies. Identification of uniquely expressed cell-surface, tumor-associated antigens (TAAs) holds promise in epithelial tumors more generally, as they can serve as ligands for a variety of therapeutics, including CAR-T cell therapy. However, TAA identification in BTCs has been limited by expression in normal liver tissue. Here, we aim to characterize the cell-surface protein transmembrane 4 L six family member 1 (TM4SF1) as a potential BTC TAA targetable by CAR-T therapy. Methods: TM4SF1 expression in BTC relative to normal hepatic/biliary tissue was characterized at the mRNA level by analyzing TCGA datasets and at the protein level by immunohistochemistry of archival primary BTC tissue. Anti-TM4SF1 CAR-T cells were evaluated through in vitro coculture assays against human-derived BTC cell lines and in a cell line-derived xenograft (CDX) model. Results: We find TM4SF1 is significantly upregulated in BTC relative to normal hepatic/biliary tissue and across BTC anatomical subtypes at the mRNA and protein level. To validate TM4SF1 as a targetable TAA in BTC, we show anti-TM4SF1 CAR-T cells demonstrate robust growth inhibition of BTC cell lines in vitro and significant anti-tumor activity against a CDX in vivo. Conclusions: Together, our data provides support for TM4SF1 as a promising TAA in BTCs that can be used for the rational development of targeted therapeutic modalities, including CAR-T cells, in a patient population with significant unmet need.

cancer biology↗

bioRxiv2026

Genome-resolved metagenomics reveals conserved, flexible and emerging symbioses across global leafhoppers

BackgroundLeafhoppers are among the most important insect vectors of plant pathogens worldwide and depend on microbial symbionts to exploit nutrient-poor phloem diets. However, most studies of leafhopper-associated microbiota have focused on a limited number of taxa or marker-gene surveys, leaving the genomic diversity, ecological organization, and functional potential of these microbial communities poorly understood. Here, we generated the Global Leafhopper Microbiome Catalog by integrating genome-resolved metagenomics from 171 leafhopper species across 11 subfamilies and 13 countries, including the first microbiomes characterized from Arctic leafhoppers. ResultsDe novo assembly and genome reconstruction generated 337 high-quality non-redundant microbial genomes and 18.6 million non-redundant genes, substantially expanding the known microbial diversity associated with Cicadellidae, including several previously undescribed bacterial lineages. Comparative analyses revealed a recurrent modular microbiome architecture composed of: (i) a conserved core of obligate nutritional symbionts, dominated by Candidatus Karelsulcia and Candidatus Nasuia; (ii) a heterogeneous layer of secondary symbionts, including Wolbachia, Arsenophonus, Rickettsia, and Diplorickettsia; and (iii) a dynamic pool of environmentally acquired bacteria. While obligate symbionts remained highly conserved across divergent hosts, secondary and environmental taxa varied substantially among species and regions, suggesting repeated acquisition shaped by ecological filtering rather than host phylogeny alone. Comparative analyses between the specialist corn leafhopper Dalbulus maidis and the more polyphagous aster leafhopper Macrosteles quadrilineatus further showed that closely related vectors can maintain conserved ancestral symbionts while harboring markedly distinct accessory microbiomes. Arctic populations contained unique microbial assemblages enriched in functions associated with cold tolerance, oxidative stress, and reproductive manipulation. In addition, we identified numerous plant-associated bacteria, including phytoplasmas, spiroplasmas, Pantoea, and Erwinia, alongside taxa with predicted nutritional and plant growth-promoting functions. ConclusionsOur findings reveal that leafhopper microbiomes are structured through the interaction of ancient obligate symbioses and flexible environmentally responsive microbial layers. This work establishes a genome-resolved framework for understanding microbiome evolution in insect vectors and highlights the potential role of microbial community structure in host adaptation, pathogen ecology, and sustainable pest management.

microbiology↗

bioRxiv2026

Nanoparticle-delivered resiquimod induces brain tumor regression in medulloblastoma and diffuse midline glioma models by interrupting paracrine growth support and activating myeloid immune signaling and phagocytosis

In pediatric brain tumors medulloblastoma (MB) and diffuse midline glioma (DMG), tumor-associated myeloid cells (TAMs) support malignant progression by secreting paracrine growth factors and suppressing local immune function. We studied the potential for reversing this cancer-supportive phenotype by stimulating TAM pathogen receptors using ResiPOx, a brain-permeant, polyoxazoline nanoparticle formulation of the TLR7/8 agonist resiquimod. ResiPOx showed blood-brain barrier penetration and anti-tumor efficacy, extending progression-free survival (PFS) in mice with MB and DMG. Integrated cellular and molecular analysis including scRNA-seq showed that ResiPOx expanded TAM populations and reprogrammed TAMs toward anti-tumoral states, blocking paracrine IGF1 signaling and inducing local cytokine signaling and phagocytosis of tumor cells. In rhesus macaques, systemic ResiPOx was well tolerated and induced brain transcriptional patterns that resembled ResiPOx responses in DMG and MB mouse models, indicating effects in non-human primates that highlight translational potential. Our data show that ResiPOx reshapes the brain tumor microenvironment to inhibit tumor growth. As a systemically administered, brain penetrant immunomodulator, ResiPOx is able to reach multifocal and unresectable brain tumors, including MB and DMG.

cancer biology↗

bioRxiv2025

BRD2 Upregulation as a Pan-Cancer Adaptive Resistance Mechanism to BET Inhibition

Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are promising cancer therapeutics that target epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors (BETi) limits their clinical utility, necessitating a better understanding of adaptive mechanisms. We identified BRD2 upregulation as a conserved response to BET inhibition across multiple cancer types and hypothesized that BRD2 compensates for BRD4 loss, sustaining essential transcriptional programs upon treatment. Consistent with this, BRD2 knockdown sensitized cancer cells to BETi in vitro, and combining BRD2 depletion and JQ1 treatment significantly impaired tumor growth in vivo. At the chromatin level, BRD2 and BRD4 ChIP-seq analysis of pancreatic cancer cells showed consistent BRD4 loss from chromatin after JQ1 treatment, while BRD2 displacement differed by sensitivity. Resistant cells maintained higher BRD2 occupancy than sensitive cells, suggesting a link between BRD2 retention and drug response. Mechanistically, NFYA mediates BRD2 upregulation as NFYA depletion attenuated BRD2 upregulation upon BETi treatment. Collectively, our findings establish BRD2 as a critical mediator of pan-cancer adaptive resistance to BETi and identify NFYA as a novel transcriptional regulator of this process. Co-targeting BRD2 or its regulatory network offers a rational strategy to enhance the durability and efficacy of BET-based therapies.

cancer biology↗

bioRxiv2025

'Candidatus Phytoplasma zeae': community-driven delineation of the maize bushy stunt phytoplasma, a Dalbulus-transmitted corn pathogen confined to the Americas

A novel phytoplasma species, Candidatus Phytoplasma zeae, is proposed based on ecological distinctiveness, vector specificity, whole-genome comparisons, and community consensus. This phytoplasma is associated with maize bushy stunt (MBS) disease in corn (Zea mays) and is transmitted exclusively by Dalbulus maidis and D. elimatus, two leafhopper species endemic to the Americas, and has been reported in Brazil, Colombia, Mexico, Peru, and several U.S. states. Here we sequenced and assembled the genome of MBS phytoplasma strains from Brazil, and U.S. to describe and propose this new species. Although the 16S rRNA gene sequence of the proposed reference strain, MBSP-BRRS, shares >99% identity with that of Ca. Phytoplasma asteris, key nucleotide polymorphisms distinguish Ca. P. zeae from other 16SrI-related phytoplasma species. Average nucleotide identity (ANI) and average amino acid identity (AAI) values between Ca. P. zeae and Ca. P. asteris are 97.70-98.00% and 96.65-96.88%, respectively, both near the established species delineation thresholds. Comparative genomic analyses revealed unique gene clusters in Ca. P. zeae associated with amino acid transport, defense mechanisms, and protein turnover, which may contribute to its specialization in corn. The ecological profile of Ca. P. zeae, including its narrow host range and restricted geographic distribution, supports its recognition as a novel species under Rule c of the IRPCM guidelines. The designation Candidatus Phytoplasma zeae is therefore proposed by members of the research community who have studied this pathogen for over a decade, with the MBSP-BrazilRS strain serving as the reference.

microbiology↗

bioRxiv2025

Uncovering diversity and climatic drivers of leafhopper-parasitoid dynamics in Canada

As climate change reshapes northern agroecosystems, leafhoppers (Hemiptera: Cicadellidae) are shifting their distributions, with implications for pest outbreaks and crop health. In Eastern Canada, we monitored strawberry farms from 2023 to 2024, collecting over 82,000 leafhoppers from 64 genera. Migratory species, Empoasca fabae and Macrosteles quadrilineatus, dominated captures, with sharp abundance increases above 16{degrees}C and 14{degrees}C, respectively, while local species declined under higher rainfall. A major finding was the first Canadian record of the corn pest Dalbulus maidis, a vector of multiple pathogens, likely introduced through long-distance dispersal. Insecticide applications generally failed to reduce leafhopper numbers, highlighting the limitations of current chemical control. Parasitism rates by Gonatopus wasps (Dryinidae), averaged ~3% but peaked in late summer at over 20%, primarily in M. quadrilineatus. Warmer temperatures and seasonal progression increased both parasitism probability and rates. Genomic analyses revealed at least three Gonatopus lineages, including the first complete mitochondrial genome for the genus from the New World, and confirmed multiple host species. We also recorded the first Canadian occurrence of G. clavipes. Our results demonstrate that parasitoids are active, climate-responsive, and capable of targeting dominant pest species. Together, these findings provide the first ecological and genomic baseline for leafhopper-parasitoid interactions in Canada. They point to the potential of conserving and enhancing native parasitoid populations as a foundation for climate-resilient, pesticide-free pest management strategies.

ecology↗

bioRxiv2024

De novo assembly and annotation of the Empoasca fabae mitochondrial genome

This study presents the assembly and annotation of the full-length mitochondrial genome for the leafhopper species Empoasca fabae Harris, 1841. The mitogenome was obtained from a contig-level assembly with the identified mitochondrial genome being 14,873 bp in length. The base composition was A (38.8%), T (39.1%), C (11.7%), and G (10.4%). The mitogenome comprised 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs), and showed a unique, non-AT-rich D-loop region. Nearly all PCGs being with an ATN start codon, while two begin with TCG and GTG. Phylogenetic analysis confirmed the placement of E. fabae within the subfamily Typhlocybinae, clustering with other species in the Empoasca genus.

genomics↗

bioRxiv2024

Discovery of novel compounds and target mechanisms using a high throughput, multiparametric phenotypic screen in a human neuronal model of Tuberous Sclerosis

Tuberous sclerosis complex (TSC) is a rare genetic disorder caused by mutations in the mTOR pathway genes TSC1 or TSC2. TSC can affect multiple organs including the brain, and most patients (75-90%) present with seizures during early childhood and intractable epilepsy throughout life. mTOR inhibitors, part of the current standard of care, lack the optimal characteristics to fully address patient phenotypes. Here, we report on the application of our all-optical electrophysiology platform for phenotypic screening in a human neuronal model of TSC. We used CRISPR/Cas9-isogenic TSC2-/- iPS cell lines to identify disease-associated changes to neuronal morphology, transcript expression and neuronal excitability. We established a robust multiparametric electrophysiological phenotype which we then validated in TSC patient-derived neurons. We used this phenotype to conduct a screen of [~]30,000 small molecule compounds in human iPS cell-derived neurons and identified chemical scaffolds that rescued the functional TSC disease parameters. Confirmed hits may act via different mechanisms than direct mTOR pathway inhibition. This strategy provides molecular starting points for therapeutic development in TSC and a framework for phenotype discovery and drug screening in other neurological disorders.

neuroscience↗

bioRxiv2023

Impact of climate change on leafhopper vectors of phytoplasmas in North America

Climate change significantly contributes to shifts in the geographical range of pests and diseases. Leafhoppers (Hemiptera: Cicadellidae), known vectors of phytoplasmas pathogens, are linked to the transmission of more than 600 diseases affecting a thousand plant species worldwide. Despite this, the potential effects of climate change on leafhopper vectors of phytoplasmas remain a critical knowledge gap. To address this gap, our study investigated the potential impact of climate change on 14 species of Nearctic leafhoppers previously associated with phytoplasma-related diseases. Using the MaxEnt species distribution algorithm and other ecological niche modeling techniques, we assessed (i) the expected species richness under current climate conditions and four future scenarios and (ii) the environmental niche similarity among these species across these scenarios. Our projections suggest that the eastern region of North America holds the potential for the highest species richness, a trend expected to persist across all future scenarios, gradually expanding eastward. Notably, our findings indicate the increasing suitability of northern Canada for more species. Network analysis further revealed a remarkable similarity in environmental niches among most leafhopper species. Moreover, across the four future scenarios, there is a tendency for an increase in this similarity. Altogether, our study underscores the potential persistent presence of Nearctic leafhoppers in their current habitats while pointing to a shift toward northern North America in future scenarios. These findings have significant implications for sustainable pest management practices, prompting a necessary discussion on strategies to mitigate climate change and pest migrations impact on agricultural systems.

ecology↗

bioRxiv2022

A phenotypic screening platform for chronic pain therapeutics using all-optical electrophysiology

Chronic pain associated with osteoarthritis (OA) remains an intractable problem with few effective treatment options. New approaches are needed to model the disease biology and to drive discovery of therapeutics. Here, we present an in vitro model of OA pain, where dorsal root ganglion (DRG) sensory neurons were sensitized by a defined mixture of disease-relevant inflammatory mediators, here called Sensitizing PAin Reagent Composition or SPARC. OA-SPARC components showed synergistic or additive effects when applied in combination and induced pain phenotypes in vivo. To measure the effect of OA-SPARC on neural firing in a scalable format for drug discovery, we used a custom system for high throughput all-optical electrophysiology. This system enabled light-based membrane voltage recordings from hundreds of neurons in parallel with single cell resolution and a throughput of up to 500,000 neurons per day, with patch clamp-like single action potential resolution. A computational framework was developed to construct a multiparameter OA-SPARC neuronal phenotype and to quantitatively assess phenotype reversal by candidate pharmacology with different mechanisms of action. We screened ~3000 approved drugs and mechanistically focused compounds, yielding data from over 1.2 million individual neurons with detailed assessment of both functional OA-SPARC phenotype rescue and orthogonal "off-target" effects. Analysis of confirmed hits revealed diverse potential analgesic mechanisms including well-known ion channel modulators as well as less characterized mechanisms including MEK inhibitors and tyrosine kinase modulators, providing validation of the platform for pain drug discovery.

neuroscience↗

bioRxiv2022

Highly Parallelized, Multicolor Optogenetic Recordings of Cellular Activity for Therapeutic Discovery Applications in Ion Channels and Disease-associated Excitable Cells

Optogenetic assays provide a flexible, scalable and information rich approach to probe compound effects for ion channel drug targets in both heterologous expression systems and associated disease relevant cell types. Despite the potential utility and growing adoption of optogenetics, there remains a critical need for compatible platform technologies with the speed, sensitivity, and throughput to enable their application to broader drug screening applications. To address this challenge, we developed the Swarm, a custom designed optical instrument for highly parallelized, multicolor measurements in excitable cells, simultaneously recording changes in voltage and calcium activities at high temporal resolution under optical stimulation. The compact design featuring high power LEDs, large numerical aperture optics, and fast photodiode detection enables all-optical individual well readout of 24-wells simultaneously from multi-well plates while maintaining sufficient temporal resolution to probe millisecond response dynamics. The Swarm delivers variable intensity blue-light optogenetic stimulation to enable membrane depolarization and red or lime-light excitation to enable fluorescence detection of the resulting changes in membrane potential or calcium levels, respectively. The Swarm can screen ~10,000 wells / day in 384-well format, probing complex pharmacological interactions via a wide array of stimulation protocols. To evaluate the Swarm screening system, we optimized a series of heterologous optogenetic spiking HEK293 cell assays for several voltage-gated sodium channel subtypes including Nav1.2, Nav1.5, and Nav1.7. The Swarm was able to record pseudo-action potentials stably across all 24 objectives and provided pharmacological characterization of diverse sodium channel blockers. We performed a Nav1.7 screen of 200,000 small molecules in a 384-well plate format with all 560 plates reaching a Z[≥]0.5. As a demonstration of the versatility of the Swarm, we also developed an assay measuring cardiac action potential and calcium waveform properties simultaneously under paced conditions using human induced pluripotent stem (iPS) cell-derived cardiomyocytes as an additional counter screen for cardiac toxicity. In summary, the Swarm is a novel high-throughput all-optical system capable of collecting information-dense data from optogenetic assays in both heterologous and iPS cell-derived models, which can be leveraged to drive diverse therapeutic discovery programs for nervous system disorders and other disease areas involving excitable cells.

bioengineering↗

bioRxiv2021

All-optical electrophysiology with improved genetically encoded voltage indicators reveals interneuron network dynamics in vivo

All-optical electrophysiology can be a powerful tool for studying neural dynamics in vivo, as it offers the ability to image and perturb membrane voltage in multiple cells simultaneously. The "Optopatch" constructs combine a red-shifted archaerhodopsin (Arch)-derived genetically encoded voltage indicator (GEVI) with a blue-shifted channelrhodopsin actuator (ChR). We used a video-based pooled screen to evolve Arch-derived GEVIs with improved signal-to-noise ratio (QuasAr6a) and kinetics (QuasAr6b). By combining optogenetic stimulation of individual cells with high-precision voltage imaging in neighboring cells, we mapped inhibitory and gap junction-mediated connections, in vivo. Optogenetic activation of a single NDNF-expressing neuron in visual cortex Layer 1 significantly suppressed the spike rate in some neighboring NDNF interneurons. Hippocampal PV cells showed near-synchronous spikes across multiple cells at a frequency significantly above what one would expect from independent spiking, suggesting that collective inhibitory spikes may play an important signaling role in vivo. By stimulating individual cells and recording from neighbors, we quantified gap junction coupling strengths. Together, these results demonstrate powerful new tools for all-optical microcircuit dissection in live mice.

neuroscience↗

bioRxiv2020

Abdominal symptoms during primary Sjögren's syndrome: a prospective study

ContextAbdominal symptoms are poorly documented during primary Sjogrens syndrome (pSS). ObjectivesTo describe abdominal symptoms among pSS patients and to assess their association with characteristics of the disease. MethodsOne hundred and fifty patients followed at Hospital and University Center of Limoges were prospectively included and were evaluated using a composite global symptom score (GSS) describing abdominal symptoms and their severity. Data concerning the clinical and biological characteristics of the pSS and abdominal disorders were also collected. ResultsNinety-five per cent of pSS patients suffered from abdominal symptoms with a median GSS of 7.5{+/-}5.5 points out of 30. More than half of the patients experienced abdominal tension (68%), upper abdominal pain (54%), abdominal discomfort (58%) and/or constipation (54%). Regarding the pSS activity ESSDAI score items, general and central nervous system involvement was associated with a high GSS. Regarding the patients symptoms ESSPRI score, there was a positive correlation with the GSS (p<0.01). Multivariate analysis showed a statistical association between a high GSS and seronegative status for SSA, gastroparesis and ESSPRI score (p<0.01 for each one). ConclusionThis study revealed that more than 90% of pSS patients suffered from abdominal symptoms. There is currently no therapeutic recommendation because of the lack of specific study and comprehension of the physiopathological mechanisms involved.

immunology↗