Biology subjects

Bender, S.

Publications and source records attributed to Bender, S..

14 recordsLinked to original sources

bioRxiv2026

Developmental Trajectories of Dynamic Brain Network Organization and Their Alteration in Tourette Syndrome

Typical brain network maturation involves an increase in network flexibility and hemispheric specialization. Tourette syndrome (TS) disrupts these trajectories, with tic severity potentially modulating deviations. This study examined theta-band EEG source connectivity states in typically developing children and children with TS. We assessed age-related trajectories and the impact of tic severity using generalized linear modeling, accounting for sex and multiple comparisons. K-means clustering identified four recurrent source connectivity states (A-D), with metrics including Coverage, representing state prevalence (proportion of time spent in each state), Average Dwell Time, an index of state stability (mean duration of stable persistence of each state), and Transition Rate Per Minute, reflecting global network flexibility (frequency of state switches per minute). In healthy controls (HC), typical maturation was characterized by increased left intra-hemisphere connectivity state stability and prevalence, decreased diffuse connectivity state stability, and rising network flexibility. TS patients exhibited deviant trajectories, including age-dependent decreasing global network flexibility across subgroups stratified by tic severity and marginally divergent diffuse activity patterns, with high-severity cases showing increased diffuse connectivity state stability. The normative patterns suggest typical motor development requiring dynamic network reconfiguration and hemispheric specialization, processes that appear altered in TS. TS patients exhibit age-dependent network rigidity across severity subgroups, as reflected by decreased transition rates, alongside severity- modulated network imbalances, indicating that tic disorders disrupt mechanisms of brain network maturation underlying motor control. These findings suggest that atypical trajectories of network stability and flexibility represent a key feature of tic pathophysiology, highlighting the role of altered network dynamics in TS during maturation.

neuroscience↗

bioRxiv2025

Preclinical characterization of AT-03, a novel Serum Amyloid P fusion protein that demonstrates pan-amyloid binding and removal

The systemic amyloidoses are progressive disorders caused by extracellular deposition of insoluble amyloid fibrils leading to organ dysfunction that often proves fatal. New therapeutics aiming at removing deposited amyloid are urgently needed to improve patient outcomes. MethodsWe developped AT-03 (originally called SAP-scFc), a fusion protein consisting of serum amyloid P-component, which binds all types of amyloid, linked to a single chain human IgG1 Fc domain. AT-03 binding to diverse types of amyloid and phagocytic activity were assessed both in vitro and in vivo. Therapeutic efficacy was evaluated in an AA mouse model. ResultsAT-03 bound with high potency to AL and ATTR human amyloid extracts. In murine models, intravenously administered AT-03 bound to AA, AL and AApoA2 amyloid, including in the heart. Ex vivo AT-03 opsonization induced phagocytosis of human AL extract by activated human THP-1 macrophages and enhanced in vivo phagocytosis in mice. A single intravenous injection of SAP-scFc induced a significant reduction of splenic amyloid in a murine model of AA amyloidosis. ConclusionsAT-03 binds many amyloid types and can promote macrophage-mediated phagocytosis of the deposits. Thus, AT-03 is a promising novel therapeutic agent for the removal of systemic amyloid.

pathology↗

bioRxiv2024

A mouse model of cardiac AL amyloidosis unveils mechanisms of tissue accumulation and toxicity of amyloid fibrils

AL amyloidosis is one of the most common types of systemic amyloidosis, caused by the deposition in tissues of fibrillar aggregates of abnormal immunoglobulin (Ig) light chain (LC), leading to organ dysfunction. The most frequent and severe forms affect the kidneys and heart, the latter being associated with a poor prognosis. Despite extensive efforts to decipher the mechanisms of fibril formation and their toxicity, the lack of reliable in vivo models hinders the study of the disease in its physiological context. We developped a transgenic mouse model producing high amounts of a human AL light chain (LC). While mice exceptionnaly develop spontaneous AL amyloidosis and do not exhibit organ toxicity due to the circulating amyloidogenic free LC, a single injection of amyloid fibrils, made up of the variable domain (VL) of the human LC, or soluble VL led to amyloid deposits in the heart, vessels, spleen and, to a lesser extent, in the kidney and other visceral tissues. AL fibrils in mice contain both full length and fragmented LC with a fragmentation pattern highly superposable to that of human AL fibrils from the same LC subgroup (IGLV6-57). They also develop an early cardiac dysfunction closely resembling the human disease with increased NT-proBNP,and activation of pathways involved in the extracellular matrix remodeling and fibrosis. Overall, this transgenic AL model closely reproduces human cardiac AL amyloidosis and shares with humans the biochemical composition of the deposits, arguing for a conserved mechanism of amyloid fibrils formation. It also shows that a partial degradation of the LC is likely required to initiate amyloid fibril formations. This model offers a new avenue for research on AL amyloidosis and fills an important gap for the preclinical evaluation of new therapies.

pathology↗

bioRxiv2024

Mapping Motor Preparation in the Developing Brain: Insights from Contingent Negative Variation and Event-related Mu Rhythm Modulation

IntroductionThe motor system shows a pronounced development throughout childhood and adolescence. The analysis of the contingent negative variation (CNV) provides valuable insights into various cognitive and motor processes, underlying cortical sources, and their development across the lifespan. MethodsWe investigated the maturation of motor preparation, pre-activation and post-processing in children and adolescents aged 5- to 16- years. EEG Data of 46 healthy right-handed subjects were recorded, using a 64-electrode high density sensor array. Subjects performed a CNV task with a directional warning cue. To assess age related developmental differences of cortical activation, analyses of event-related potentials (ERPs), mu-rhythm (de)synchronization and source analysis were applied. ResultsChildren showed increased reaction times and committed more errors than adolescent subjects. Motor preparation and post-processing were characterized by a developmental increase of cortical activity related to the supplementary motor area (SMA). Young children showed a pronounced sensory post processing during orienting response (early CNV) that decreased with age. In contrast to previous research in young adults, adolescent subjects showed no contralateral activation of motor areas during motor preparation (late CNV) yet. Furthermore, there was an observed decline in motor post processing with maturation. ConclusionThe results indicate a prolonged maturation of cortical scalp areas associated with motor control up into late adolescence or early adulthood. With age, the activation of mid-frontocentral regions associated with the SMA becomes more pronounced during motor planning and response evaluation. Qualitatively distinct cortical activation patterns of young subjects suggest immature supplementary-, pre- and primary motor areas and might be a primary cause for age-related increasing efficiency of motor action control.

developmental biology↗

bioRxiv2023

Disruption of immunoglobulin heavy and light chain assembly by antisense oligonucleotides impairs protein homeostasis and myeloma cell survival

Multiple myeloma (MM) is related to the accumulation of malignant plasma cells (PCs) in the bone marrow. MM accounts for approximatively 10% of hematological malignancies and despite major improvement in therapies and outcomes, relapses will virtually occur in all patients. Usually, the disease goes along with an excess production of a monoclonal immunoglobulin (Ig) component by the tumor PC clone. However, many questions remain regarding the consequences of a deregulated Ig production on PC survival. Recent advances in RNA-based therapy using antisense oligonucleotides (ASO) prompted us to examine the impact of altered Ig heavy to light chain (HC/LC) ratios in MM cells. We designed a pan IgG subclasses specific ASO targeting a consensus sequence found in the polyadenylation signal (PAS) of all secreted IGHG mRNAs (IgG-ASO). Remarkably, treatment with this compound strongly decreased IgG secretion in MM cell lines and patient cells. Consistent with a deregulated HC/LC ratio, a dose-dependent excess of free-LCs (as monomers and dimers) was observed in myeloma cells treated with IgG-ASO, compared to an irrevelant control ASO (CTRL). RNA-seq profiles further indicated that the expression of genes involved in cellular metabolism, unfolded protein response (UPR) and cell death pathways were altered after treatment with IgG-ASO. Interestingly, impaired survival of primary IgG-expressing cells isolated from MM patients was achieved upon treatment with IgG-ASO, whereas no major effect was observed for healthy cells. Altogether, our data provide evidence for efficient inhibition of IgG secretion upon ASO treatment and suggest that an excess of free-LC due to disruption of HC/LC stoichiometry is toxic for MM cells expressing complete Ig. Such RNA-based strategies targeting PC in an Ig isotype-dependent manner could open new avenues for selective therapeutic approaches in PC dyscrasias.

immunology↗

bioRxiv2023

Fecal microbiomics biomarkers for Chronic Wasting Disease

Chronic wasting disease (CWD) is a naturally occurring prion disease in cervids that has been rapidly proliferating in the US. Here we investigated a potential link between CWD infection and gut microbiome by analyzing 50 fecal samples obtained from CWD-positive animals of different sexes from various regions in the US, compared to 50 CWD-negative controls using high throughput sequencing of the 16S ribosomal RNA and targeted metabolomics. Our analysis reveals promising trends in the gut microbiota that could potentially be CWD-dependent, including several bacterial taxa at each rank level, as well as taxa pairs, that can differentiate between CWD-negative and CWD-positive deer. At each rank level, these taxa and taxa pairs could facilitate identification of around 70% of both the CWD-negative and the CWD-positive samples. Our results provide a potential tool for diagnostics and surveillance of CWD in the wild, as well as conceptual advances in our understanding of the disease. ImportanceThis is a comprehensive study that tests the connection between the composition of the gut microbiome in deer in response to Chronic Wasting Disease (CWD). We analyzed 50 fecal samples obtained from CWD-positive animals compared to 50 CWD-negative controls to identify CWD-dependent changes in the gut microbiome, matched with the analysis of fecal metabolites. Our results show promising trends suggesting that fecal microbial composition can directly correspond to CWD disease status. These results point to microbial composition of the feces as a potential tool for diagnostics and surveillance of CWD in the wild, including non-invasive CWD detection in asymptomatic deer and deer habitats, and enable conceptual advances in our understanding of the disease.

microbiology↗

bioRxiv2022

A dual function for the chromatin organizer Special A-T rich Binding Protein 1 in B-lineage cells

SATB1 (Special A-T rich Binding protein 1) is a cell type specific factor involved in chromatin remodelling events that participate in the regulation of the genetic network in developing T cells and neurons. In T cells, SATB1 is a key factor required for lineage commitment, VDJ recombination, development and maturation. In B cells, SATB1 is described as binding to the MARs-E{micro} regions of the IgH locus. Considering that its expression varies during differentiation, the involvement of this factor needed to be clarified in B cells. Using a KO mouse model deleting SATB1 from the pro-B cell stage, we were able to examine the consequences of SATB1 deletion in naive and activated B cell subsets. Our model indicates firstly that SATB1 is not essential for B cell development and the establishment of a broad IgH repertoire. Second, we show that this factor exhibits an ambivalent function in mature B cells, acting sequentially as a positive and negative regulator of Ig gene transcription in naive and activated cells, respectively. Third, our study indicates that the negative regulatory function of SATB1 in B cells extends to the germinal center response in which this factor limits somatic hypermutation of Ig genes. This finding suggests that SATB1 may limit the introduction of unwanted mutations into B cells.

immunology↗

bioRxiv2022

The IgH Eμ-MAR regions promote UNG-dependent error-prone repair to optimize somatic hypermutation

Two scaffold/matrix attachment regions (5- and 3-MARsE) flank the intronic core enhancer (cE) within the immunoglobulin heavy chain locus (IgH). Besides their conservation in mice and humans, the physiological role of MARsE is still unclear and their involvement in somatic hypermutation (SHM) has never been deeply evaluated. By analysing a mouse model devoid of MARsE, we observed an inverted substitution pattern: SHM being decreased upstream from cE and increased downstream of it. Strikingly, the SHM defect induced by MARsE-deletion was accompanied by an increase of sense transcription of the IgH V region, excluding a direct transcription-coupled effect. Interestingly, by breeding to DNA repair-deficient backgrounds, we showed that the SHM defect, observed upstream from cE in this model, was not due to a decrease in AID deamination but rather the consequence of a defect in base excision repair-associated unfaithful repair process. Our study pointed out an unexpected "fence" function of MARsE regions in limiting the error-prone repair machinery to the variable region of Ig gene loci.

immunology↗

bioRxiv2020

New models to study plasma cells in mouse based on the restriction of IgJ expression to antibody secreting cells.

Plasma cells (PC) represent the last stage of B cell development and are mainly characterized by their capacity of secreting large quantities of antibodies. They can be implicated in a broad-spectrum of neoplastic disorders, including Multiple Myeloma, Waldenstrom macroglobulinemia or Monoclonal Gammopathy of Clinical Significance, all characterized by the abnormal proliferation of a PC clone. Up to date, there are only few reporter models to specifically follow PC development, migration and homing in mouse and none allowing the genetic manipulation of these cells. We created a transgenic mouse model in which a green fluorescent protein gene was placed under the control of the well-characterized regulatory elements of the murine immunoglobulin J (IgJ) chain locus. Thanks to this model, we demostrated that IgJ is an early and specific marker of antibody secreting cells (ASCs) and appears before the expression of CD138, making it a good candidate to targeted genetic modifications of plasma cells. Therefore, a conditional deletion model using a Tamoxifen-dependent Cre recombinase inserted into the IgJ locus was characterized. Using a reporter model, we showed that, in contrast with existing models of B cell lineage genetic modification, the activity of the CRE recombinase only affects ASCs after tamoxifen treatment. Additionally, we used this model in a functional in vitro assay, to show that Ig modifications directly affect plasma cell survival. These two new mouse models, IgJGFP and IgJCreERT2 represent exquisite tools to study PCs. In pathology, the IgJCreERT2model opens new frontiers for in vivo genetic modifications of PCs to better reflect the pathophysiology of PC-related diseases.

immunology↗

bioRxiv2019

Multiplexed single-cell profiling of post-perturbation transcriptional responses to define cancer vulnerabilities and therapeutic mechanism of action

Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate or the expression of a marker gene. Information-rich assays, such as gene-expression profiling, are generally not amenable to efficient profiling of a given perturbation across multiple cellular contexts. Here, we developed MIX-Seq, a method for multiplexed transcriptional profiling of post-perturbation responses across a mixture of samples with single-cell resolution, using SNP-based computational demultiplexing of single-cell RNA-sequencing data. We show that MIX-Seq can be used to profile responses to chemical or genetic perturbations across pools of 100 or more cancer cell lines, and combine it with Cell Hashing to further multiplex additional experimental conditions, such as multiple post-treatment time points or drug doses. Analyzing the high-content readout of scRNA-seq reveals both shared and context-specific transcriptional response components that can identify drug mechanism of action and can be used to predict long-term cell viability from short-term transcriptional responses to treatment.

cancer biology↗

bioRxiv2019

Full-length immunoglobulin high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

POEMS syndrome is a rare multisystem disease due to an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected, due to the highly restrictive usage of two {lambda} variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations following PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (RACE-RepSeq), we detected a {lambda} LC monoclonal expansion in the bone marrow (BM) of 85% of patients with POEMS syndrome, including some in whom bone marrow tests routinely performed to diagnose plasma cell dyscrasia failed to detect {lambda}+ monoclonal PCs. Twenty-four of the 30 LC clonal sequences found (80%) were derived from the IGLV1-40 and IGLV1-44 germline genes, two from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid and specific tool to detect low-abundance PC clones in BM, and assign them to POEMS syndrome, with all the consequences for therapeutic options hereby.

immunology↗

bioRxiv2019

Studying global processing in autism and attention-deficit/hyperactivity disorder with gaze movements: The example of a copying task

Recent discussions in the literature, along with the revision of the Diagnostic and Statistical Manual (DSM) [2], suggest aetiological commonalities between the highly comorbid Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). Addressing this discussion requires studying these disorders together by comparing constructs typical to each of them. In the present study, we investigate global processing, known to be difficult for participants with ASD, and Intra-Subject Variability (ISV), known to be consistently increased in participants with ADHD, in groups, aged 10-13 years, with ADHD (n=25), ASD without comorbid ADHD (ASD-) (n=13) and ASD with ADHD (ASD+) (n=18) in comparison with a typically developing group (n=22). A Copying task, typically requiring global processing and in this case particularly designed using equally complex stimuli to also measure ISV across trials, was selected. Oculomotor measures in this task proved to be particularly sensitive to group differences. While increased ISV was not observed in the present task in participants with ADHD, both ASD groups needed to look longer on the figure to be drawn, indicating that global processing takes longer in ASD. However, the ASD+ group needed to fixate on the figure only between drawing movements, whereas the ASD-group needed to do this throughout the drawing process. The present study provides evidence towards ASD and ADHD being separate, not-overlapping, disorders. Since the pure ASD-group was affected more by central coherence problems than the ASD+ group, it may suggest that neuropsychological constructs interact differently in different clinical groups and sub-groups.

neuroscience↗

bioRxiv2019

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

Light chain deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin (Ig) light chain (LC), leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse Ig kappa locus, ensuring its production by all plasma cells. High free LC levels were achieved after backcrossing with mice presenting increased plasma cell differentiation and no Ig heavy chain (HC) production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria and finally, kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on plasma cells demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function, but partially reversed kidney lesions. Finally, transcriptome analysis of pre-sclerotic glomeruli revealed that proliferation and extracellular matrix remodelling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy.

pathology↗

bioRxiv2017

Dissecting telomere maintenance mechanisms in pediatric glioblastoma

Pediatric glioblastoma (pedGBM) represent a highly malignant primary brain tumor with recurrent mutations in the chromatin remodeler ATRX and the histone variant H3.3 that is typically associated with a fatal outcome. ATRX acts as suppressor of the alternative lengthening of telomeres (ALT) pathway, which is frequently activated in pedGBM. However, telomere features of pedGBMs have not been studied in detail, and ALT-positive model cell lines are lacking. Here, we systematically characterized a panel of pedGBM models that carry a representative set of recurrent genomic mutations for a variety of telomere features. These included the presence of ALT-associated promyelocytic leukemia nuclear bodies and C-circles, a specific type of extrachromosomal telomeric repeats, the telomere repeat content, and phosphorylation of histone H3.3 at serine 31. From an integrated analysis of seven pedGBM cell lines and 57 primary tumor samples we identified cell lines and tumors that represent the different telomere maintenance mechanisms and conclude the following: (i) A positive signal in the C-circle assay is a reliable ALT marker. (ii) ALT features occur heterogeneously and one pedGBM subgroup uses a non-canonical ALT mechanism in the presence of wild-type ATRX. (iii) The spreading of H3.3S31 phosphorylation during mitosis is associated with loss of ATRX but not with ALT per se. (iv) In contrast to a previous study in glioma stem cells, we did not find a hypersensitivity of ALT cells towards the ATR inhibitor VE-821. (v) ALT-positive pedGBMs can be reliably identified from a classification scheme developed here that evaluates various combinations of cytogenetic and/or genomic data. Thus, our findings elucidate further details of the ALT pathway in pedGBMs, provide valuable models for evaluating ALT targeted therapies in a preclinical setting, and introduce an ALT classification scheme for primary tumor samples.

cancer biology↗