Biology subjects

Pelletier, M.

Publications and source records attributed to Pelletier, M..

10 recordsLinked to original sources

bioRxiv2026

NEURAL CORRELATES OF SUBJECTIVE FOOD VALUATION IN THE CONTEXT OF BARIATRIC SURGERY

Objective: To examine changes in the neural valuation of high- versus low-calorie stimuli following bariatric surgery and determine whether these changes relate to weight loss at 24 months. Methods: Adults undergoing bariatric surgery completed fMRI scans before surgery and at 4, 12 and 24 months post-surgery while performing the Becker-DeGroot-Marschak auction task to assess willingness-to-pay (WTP) for food stimuli. Linear mixed-effect models tested longitudinal changes in WTP-related blood oxygen level-dependent (BOLD) associations and their interactions with total weight loss at 24 months. Results: WTP for high-calorie foods decreased significantly after surgery, whereas valuation of low-calorie foods remained stable. At 4 months, WTP-BOLD associations for high- versus low-calorie stimuli were enhanced within the frontoparietal control network and right lateral orbitofrontal cortex relative to pre-surgery. These early postoperative changes did not correlate with 24-month weight loss. Instead, greater 24-month weight loss correlated with both pre-surgical and long-term changes (24 months versus pre-surgery) in WTP-BOLD associations within the precuneus, inferior parietal cortex and visual cortex. Conclusion: Bariatric surgery induces early reductions in the valuation of high-calorie foods, potentially through enhanced cognitive control and aversive processing. However, long-term weight-loss success appears more strongly related to trait-like neural differences in self-referential and attentional processing.

neuroscience↗

bioRxiv2026

Transcription Factor Subtype Governs Response and Resistance to DLL3-Directed T-Cell Engagement in Small Cell Lung Cancer

Although small cell lung cancer (SCLC) comprises transcription factor (TF)-defined molecular subtypes (ASCL1, NEUROD1, POU2F3), the extent to which these subtypes predict response to clinically effective therapy in patients--and whether therapy can select for subtype switching--remains unknown. The recent approval of the DLL3xCD3 bispecific T-cell engager tarlatamab represents one of the first meaningful advances in relapsed small cell lung cancer (SCLC) in decades, yet responses remain heterogeneous and resistance is inevitable. Here, we inferred SCLC gene expression from circulating chromatin in prospectively collected patient plasma (46 patients; 167 samples), enabling interrogation of response and acquired resistance to tarlatamab. Parallel development of the first immunocompetent syngeneic mouse model to study tarlatamab response and resistance enabled functional validation. Across species, findings converged on a central principle: TF subtype governs both initial response and acquired resistance. Therapeutic response was significantly associated with ASCL1-subtype tumors, whereas NEUROD1-subtype tumors exhibited inferior responses and POU2F3-subtype tumors were uniformly resistant, consistent with DLL3 being a direct ASCL1 transcriptional target and most highly expressed in ASCL1-positive tumors. Strikingly, one mode of acquired resistance revealed therapeutic selection for a NEUROD1-high state with concomitant DLL3 downregulation. Other resistant tumors exhibited enrichment of regulatory and exhausted T-cell programs, highlighting tarlatamabs dual-targeting mechanism of action. Together, these results reveal that tarlatamab exerts selective pressure against ASCL1-driven lineages, facilitating resistance through loss of an antigen intrinsically linked to that state. These findings underscore the clinical relevance of TF-defined molecular subtypes in human SCLC. More broadly, they highlight the power of integrating longitudinal in vivo plasma transcriptional profiling from patient plasma with functional mouse modeling to uncover clinical and biological mechanisms of response and resistance to cell-surface-targeted therapies.

cancer biology↗

bioRxiv2026

Mitochondrial Transplantation in the Eye: A Review and Evaluation of Surgical Approaches

PurposeMitochondrial dysfunction contributes to major blinding diseases, including age-related macular degeneration and glaucoma. Although mitochondrial transplantation has shown therapeutic potential in multiple organ systems, translation to the eye remains limited, partly due to uncertainty regarding optimal delivery. We summarize the biologic rationale and preclinical evidence supporting ocular mitochondrial transplantation and present feasibility data evaluating clinically relevant delivery routes. MethodsWe conducted a focused narrative review of ocular mitochondrial transplantation. For feasibility experiments, mitochondria with an endogenous fluorescent dye were isolated from liver donor mice. Postnatal day 7 pups received subretinal injections, and adult CD1 mice received intravitreal injections, including optic nerve head directed delivery. Eyes were analyzed using fluorescence microscopy and immunohistochemistry. Mitochondrial uptake was assessed in cultured retinal pigmental epithelial (RPE) cells using co-incubation assays. Suprachoroidal delivery feasibility was evaluated in cadaveric human near-real surgical specimens using a novel dedicated suprachoroidal injector. ResultsThe literature on ocular mitochondrial transplantation remains limited and consists primarily of small preclinical studies using intravitreal delivery and imaging-based detection. In our experiments, intravitreal delivery produced donor signals predominantly within inner retinal layers, with enrichment along retinal nerve fiber bundles when directed toward the optic nerve head. Cultured RPE cells demonstrated dose-dependent uptake of exogenous mitochondria. Subretinal delivery localized donors signal to the RPE and adjacent outer retina. Suprachoroidal injections demonstrated procedural feasibility with reliable access to the suprachoroidal space and visible injectate distribution. ConclusionsOcular mitochondrial transplantation is in an early stage of investigation. Our feasibility data indicate that established posterior-segment delivery routes expose distinct retinal compartments and that route selection strongly influences anatomic distribution. Further studies are needed to verify intracellular uptake, define dosing and durability, and evaluate safety in disease-relevant models.

cell biology↗

bioRxiv2026

SynAPSeg: A novel dataset and image analysis framework for deep learning-based synapse detection and quantification

Synapses are the fundamental units of neural computation, yet quantifying their organization across circuit-level scales remains a critical bottleneck in neuroscience. While advances in fluorescent labeling and imaging can generate vast datasets, analysis is often the limiting factor. Several deep learning-based tools have been proposed to ameliorate these issues. However, existing applications primarily focus on dendritic spines and lack robust solutions for segmenting synaptic puncta in dense tissue preparations. To address this, we introduce SynAPSeg, which encompasses an open-source framework for deep learning-based analysis and, to the best of our knowledge, the first large-scale, publicly available instance segmentation dataset specifically curated for synaptic puncta. We use this dataset to train deep learning models that reach the performance of human experts across a unique benchmark dataset. SynAPSeg integrates these models into an interactive interface, with support for multi-dimensional data, enabling fully automated segmentation and quantification pipelines alongside an annotation module for refinement and validation. We demonstrate the frameworks scalability by performing the first comprehensive mapping of nearly 4 million excitatory postsynaptic PSD95 puncta within inhibitory interneurons across the dorsal hippocampus, revealing regional differences in synapse properties. Finally, we show SynAPSegs utility for 3D quantification by applying these models to study aging-associated synaptic changes in CA1 parvalbumin (PV)-positive inhibitory neurons. Through this approach, we uncover a reduction in PSD95 density along PV dendrites in the aged CA1, indicating reduced glutamatergic recruitment of PV neurons which could contribute to age-related cognitive decline. Collectively, these results demonstrate that SynAPSeg provides a scalable solution for comprehensively studying synaptic architecture in health and disease.

neuroscience↗

bioRxiv2026

Late gestational exposure to flutamide alters stromal composition and immune landscape in the rat mammary gland during pre-puberty, peri-puberty, and adulthood

Perinatal development of the mammary gland is regulated by hormonal signals that influence cell proliferation, extracellular matrix remodeling, immune cell recruitment, and intracellular signaling. While the role of estrogen in mammary gland development is well established, the impact of androgens remains less understood. To address this gap, we inhibited androgen signaling in utero using the anti-androgen flutamide (FLU) and investigated the effects on mammary gland development in rats. Using an integrative strategy combining histology, transcriptomics, lipidomics, cytokine profiling, and high-resolution imaging, mammary tissue were analyzed at pre-puberty (postnatal days (PND) 21), peri-puberty (PND46), and adulthood (PND9O). FLU exposure induced subtle, yet significant, alterations in mammary morphology and molecular signatures. At PND2l, the FLU exposed group exhibited an increased number of adipocytes with reduced size. Transcriptomic analysis revealed differentially expressed genes at PND2l and enrichment in pathways related to androgen response and immune signaling, but minimal changes at later developmental stages. Lipidomic profiling showed transient disruption in long-chain fatty acid composition at early developmental stages. Cytokine profiling revealed a reduced adaptive immune response at PND46 and PND9O, and second harmonic generation imaging demonstrated changes in collagen fiber orientation and density across all developmental stages. These data indicate that prenatal androgen signaling is essential for proper stromal development and the establishment of early transcriptional networks in the mammary gland, with only minor long-term effects on glandular architecture in adult nulliparous females.

pharmacology and toxicology↗

bioRxiv2025

An in utero exposure to the synthetic estrogen diethylstilbestrol affects the fat pad composition in post-natal mammary glands

In utero exposure to the synthetic estrogen diethylstilbestrol (DES) has been linked to developmental abnormalities and elevated breast cancer risk in adulthood in human and rodent models. While the impact of DES on the mammary epithelium has been thoroughly investigated, its effect on the other cell types of the mammary gland remains understudied. Here, given that the mammary gland development is strongly associated with its microenvironment, we aimed to investigate how in utero DES exposure alters the mammary glands stromal and immune function across key developmental stages. To achieve this aim, timed-pregnant rats were gavaged daily with DES or vehicle from gestation days 16-21, and female offspring mammary glands were analyzed at pre-puberty (postnatal day 21 (PDN21)), puberty (PND46), and adulthood (PND90). We assessed morphological and extracellular matrix changes, performed transcriptomic cell-type enrichment analysis, measured cytokine expression, and quantified immune cell populations. DES-exposed mammary glands exhibited pronounced stromal remodeling, including increased collagen deposition and orientation by adulthood. Gene expression profiling indicated DES-induced stage-specific immune alterations: immune cell signatures were enriched at PND21 and PND90 but diminished at PND46. Correspondingly, DES increased macrophage populations at PND21 while reducing T-lymphocyte numbers at PND46 and PND90. DES exposure also dysregulated inflammatory cytokine/chemokine expression in adult glands, suggesting a persistent inflammatory environment. In conclusion, in utero exposure to an estrogenic compound can reprogram mammary development, inducing long-term changes in the extracellular matrix and immune landscape. These disruptions to stromal-immune homeostasis may impair normal mammary morphogenesis and increase susceptibility to breast pathologies later in life.

pharmacology and toxicology↗

bioRxiv2025

Acquired Neutrophil Dysregulation in Systemic Lupus Erythematosus: A Central Role for Fc gamma Receptor Engagement

PurposeSystemic lupus erythematosus is an autoimmune disease hallmarked by a plethora of autoantibodies, interferon-signature, auto-immune complexes, dysregulation of soluble factors in circulation, and abnormal neutrophils. We characterized the neutrophil phenotype in a cohort of lupus patients and assessed the implication of the cells environment. MethodsBlood samples were analyzed for neutrophil expression of surface markers and viability, by flow cytometry. Neutrophils from healthy volunteers were stimulated with serum samples from lupus patients. Plasma samples were subjected to multiplex analysis. Whole blood and isolated neutrophils were stimulated with lupus-relevant soluble factors or with heat-aggregated IgGs that mimic the engagement of Fc gamma (Fc{gamma}) receptors by immune complexes, for viability and activation analysis. ResultsLupus neutrophils displayed significant alterations in the expression of surface markers of adhesion, complement regulation, degranulation, and immune complex response. They also had reduced viability and increased apoptosis. Stimulation of healthy neutrophils with lupus serum increased apoptosis. Lupus-relevant soluble factors accelerated neutrophil apoptosis. Heat-aggregated IgGs mirrored most of the key alterations in viability and surface marker expression observed in lupus neutrophils. ConclusionThis study offers a prototypical phenotype for neutrophils in lupus, characterized by shortened viability, partial degranulation, heightened adhesion capacity, and responsiveness to complement activation. It also points to Fc{gamma} receptors engagement as a major driver of the phenotype observed herein. Finally, results emphasize the therapeutic potential of targeting neutrophil-immune complex interactions and the inflammatory plasma milieu in lupus, from which neutrophil dysfunction is largely acquired. HIGHLIGHTSO_LINeutrophils from patients with lupus exhibit abnormal phenotype and viability. C_LIO_LIAnalysis of plasmas in lupus reveals altered levels of analytes. C_LIO_LIStimulation of healthy whole blood with a model of immune complexes reproduces most of the neutrophil phenotypic abnormalities observed in lupus. C_LIO_LINeutrophil abnormalities in lupus are largely acquired, rather than representing subsets. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/653336v2_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@18547c1org.highwire.dtl.DTLVardef@129f495org.highwire.dtl.DTLVardef@178a36corg.highwire.dtl.DTLVardef@131158b_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Contribution of markers of adiposopathy and adipose cell size in predicting insulin resistance markers in women of varying age and adiposity

Adipose tissue (AT) dysfunctions, such as adipocyte hypertrophy, macrophage infiltration and secretory adiposopathy (low plasma adiponectin/leptin, A/L, ratio), associate with metabolic disorders. However, no study has compared the relative contribution of these markers to cardiometabolic risk in women of varying age and adiposity. Body composition, regional AT distribution, lipid-lipoprotein profile, glucose homeostasis and plasma A and L levels were determined in 67 women (age: 40-62 years; BMI: 17-41 kg/m2). Expression of macrophage infiltration marker CD68 and adipocyte size were measured from subcutaneous abdominal (SCABD) and omental (OME) fat. AT dysfunction markers correlated with most lipid-lipoprotein levels. The A/L ratio was negatively associated with fasting insulinemia and HOMA-IR, while SCABD or OME adipocyte size and SCABD CD68 expression were positively related to these variables. Combination of tertiles of largest adipocyte size and lowest A/L ratio showed the highest HOMA-IR. Multiple regression analyses including these markers and TAG levels revealed that the A/L ratio was the only predictor of fasting insulinemia and HOMA-IR. The contribution of the A/L ratio was superseded by adipose cell size in the model where the latter replaced TAGs. Finally, leptinemia was a better predictor of IR than adipocyte size and the A/L ratio in our participant sample.

cell biology↗

bioRxiv2021

Spontaneous Neural Activity Changes after Bariatric Surgery: a resting-state fMRI study

1.BackgroundMetabolic disorders associated with obesity could lead to alterations in brain structure and function. Whether these changes can be reversed after weight loss is unclear. Bariatric surgery provides a unique opportunity to address these questions because it induces marked weight loss and metabolic improvements which in turn may impact the brain in a longitudinal fashion. Previous studies found widespread changes in grey matter (GM) and white matter (WM) after bariatric surgery. However, findings regarding changes in spontaneous neural activity following surgery, as assessed with the fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity of neural activity (ReHo), are scarce and heterogenous. In this study, we used a longitudinal design to examine the changes in spontaneous neural activity after bariatric surgery (comparing pre- to post-surgery), and to determine whether these changes are related to cardiometabolic variables. MethodsThe study included 57 participants with severe obesity (mean BMI=43.1{+/-}4.3kg/m2) who underwent sleeve gastrectomy (SG), biliopancreatic diversion with duodenal switch (BPD), or Roux-en-Y gastric bypass (RYGB), scanned prior to bariatric surgery and at follow-up visits of 4 months (N=36), 12 months (N=29), and 24 months (N=14) after surgery. We examined fALFF and ReHo measures across 1022 cortical and subcortical regions (based on combined Schaeffer-Xiao parcellations) using a linear mixed effect model. Voxel-based morphometry (VBM) based on T1-weighted images was also used to measure GM density in the same regions. We also used an independent sample from the Human Connectome Project (HCP) to assess regional differences between individuals who had normal-weight (N=46) or severe obesity (N=46). ResultsWe found a global increase in the fALFF signal with greater increase within dorsolateral prefrontal cortex, precuneus, inferior temporal gyrus, and visual cortex. This effect was more significant 4 months after surgery. The increase within dorsolateral prefrontal cortex, temporal gyrus, and visual cortex was more limited after 12 months and only present in the visual cortex after 24 months. These increases in neural activity measured by fALFF were also significantly associated with the increase in GM density following surgery. Furthermore, the increase in neural activity was significantly related to post-surgery weight loss and improvement in cardiometabolic variables, such as insulin resistance index and blood pressure. In the independent HCP sample, normal-weight participants had higher global and regional fALFF signals, mainly in dorsolateral/medial frontal cortex, precuneus and middle/inferior temporal gyrus compared to the obese participants. These BMI-related differences in fALFF were associated with the increase in fALFF 4 months post-surgery especially in regions involved in control, default mode and dorsal attention networks. ConclusionsBariatric surgery-induced weight loss and improvement in metabolic factors are associated with widespread global and regional increases in neural activity, as measured by fALFF signal. These findings alongside the higher fALFF signal in normal-weight participants compared to participants with severe obesity in an independent dataset suggest an early recovery in the neural activity signal level after the surgery.

neuroscience↗

bioRxiv2019

Neuroanatomical Changes in White and Grey Matter after Sleeve Gastrectomy

BackgroundMRI studies show that obese adults have reduced grey (GM) and white matter (WM) tissue density as well as altered WM integrity. It remains to be examined if bariatric surgery induces structural brain changes. The aim of this study is to characterize GM and WM density changes in a longitudinal setting, comparing pre- and post-operation and to determine whether these changes are related to inflammation and cardiometabolic markers.\n\nMethods29 severely obese participants (age: 45.9{+/-}7.8 years) scheduled to undergo sleeve gastrectomy (SG) were recruited. High-resolution T1-weighted anatomical images were acquired 1 month prior to as well as 4 and 12 months after surgery. GM and WM densities were quantified using voxel-based morphometry (VBM). Circulating lipid profile, glucose, insulin and inflammatory markers (interleukin (IL)-6, C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP) were measured at each time point. A linear mixed effect model was used to compare brain changes before and after SG, controlling for age, gender, initial BMI and diabetic status. To assess the associations between changes in adiposity, metabolism and inflammation and changes in GM or WM density, the mean GM and WM densities were extracted across all the participants using atlas, and linear mixed-effect models were used.\n\nResultsAs expected, weight, BMI, waist circumference and neck circumference significantly decreased after SG compared with baseline (p<0.001 for all). A widespread increase in WM density was observed after surgery, particularly in the cerebellum, brain stem, cerebellar peduncle, cingulum, corpus callosum and corona radiata (p<0.05, after FDR correction). Significant increases in GM density were observed 4 months after SG compared to baseline in several brain regions such as the bilateral occipital cortex, temporal cortex, precentral gyrus and cerebellum as well as right fusiform gyrus, right hippocampus and right insula. These GM and WM increases were more pronounced and widespread after 12 months and were significantly associated with post-operative weight loss and the improvement of metabolic alterations. Our linear mixed-effect models also showed strong associations between post-operative reductions in LBP, a marker of inflammation, and increased WM density. To confirm our results, we tested whether the peak of each significant region showed BMI-related differences in an independent dataset (Human Connectome Project). We matched a group of severely obese individuals with a group of lean individuals for age, gender and ethnicity. Severe obesity was associated with reduced WM density in the brain stem and cerebellar peduncle as well as reduced GM density in cerebellum, regions that significantly changed after surgery (p<0.01 for all clusters).\n\nConclusionsBariatric surgery-induced weight loss and improvement in metabolic alterations is associated with widespread increases in WM and GM densities. These post-operative changes overlapped with baseline brain differences between severely obese and normal-weight individuals, which may suggest a recovery of WM and GM alterations after bariatric surgery.

neuroscience↗