Biology subjects

Mansour, M.

Publications and source records attributed to Mansour, M..

10 recordsLinked to original sources

bioRxiv2026

Dissecting the Role of the Lateral Entorhinal Cortex in Memory Interference

Memory interference occurs when an older memory competes with a newer memory that shares similar features 1. The hippocampal-entorhinal system is essential for memory 2,3, and the entorhinal cortex has been implicated in interference using the latent inhibition paradigm 4. In latent inhibition, prior non-reinforced exposure to a stimulus reduces the conditioned response later elicited when that same stimulus is paired with an aversive or appetitive outcome 5. Competition-based models propose that latent inhibition arises because the memory that the pre-exposed stimulus was inconsequential competes during retrieval with the memory that the same stimulus predicts an unconditioned stimulus 6. Although entorhinal cortex lesions or inactivation impair latent inhibition 7-10, the specific contribution of the lateral entorhinal cortex (LEC) remains unclear. The LEC provides non-spatial and cue-related input to the hippocampus 11 and has been implicated in associative memory 12,13. LEC function also declines with age 14,15, a period when memory interference increases 16. Here, we used chemogenetics to transiently inhibit excitatory neurons in the LEC during retrieval in a latent inhibition paradigm. LEC inhibition did not impair conditioned fear responses to a non-pre-exposed tone, indicating that retrieval of the tone-shock association remained intact. However, LEC inhibition attenuated latent inhibition by increasing conditioned fear responses to a pre-exposed tone. Together, these findings suggest that the LEC supports retrieval of prior inconsequential stimulus memories that compete with newer conditioned associations, providing a potential mechanism by which age-related LEC dysfunction may contribute to increased memory interference. HighlightsO_LIPre-exposure to a tone attenuates retrieval of a tone-evoked conditioned fear response, revealing latent inhibition C_LIO_LILateral entorhinal cortex inhibition does not impair fear-memory retrieval in non-pre-exposed animals C_LIO_LIThe lateral entorhinal cortex is required for the expression of latent inhibition during retrieval C_LIO_LIThe lateral entorhinal cortex contributes to memory interference during retrieval of stimuli with conflicting associations C_LI In BriefGhazy et al. show that the lateral entorhinal cortex (LEC) is required for latent inhibition during retrieval, in which prior tone exposure attenuates later fear responding to that same tone. Because LEC inhibition does not impair tone-evoked conditioned fear responding, these findings indicate that the LEC contributes to memory interference when the same stimulus has conflicting associations.

neuroscience↗

bioRxiv2026

The Relationship between Institutional Prestige, Journal Impact Factor, and Sample Size in fMRI Studies of Memory: A Systematic Review

Low statistical power remains a persistent concern in functional magnetic resonance imaging (fMRI) research, largely due to small sample sizes. Although prior work has documented gradual increases in sample size over time, it remains unclear whether structural factors in the publication process are associated with study design characteristics such as sample size. This review addresses this gap by analyzing a large sample of fMRI studies to assess how institutional prestige, journal impact factor, and journal review practices are associated with sample size. We analyzed articles published in 2021-2024 reporting new fMRI data collection in adult humans and including a measure of memory. We found studies with specialized populations, such as patient populations, had smaller sample sizes, as did studies with task-based designs compared to resting-state designs. We also found larger sample sizes were associated with journals with a double-blind review process. Institutional prestige was positively associated with sample size such that more highly ranked institutions tended to have larger samples, but there was no interaction between review type (single-vs. double-blind) and prestige, indicating this difference is not likely due to reviewer bias. Journal impact factor was not associated with sample size, however institutional prestige score predicted journal impact factor. These results suggest structural factors at the institutional level likely have a stronger influence on published study sample size than reviewer practices or biases.

neuroscience↗

bioRxiv2025

Neuroblastoma-associated ALK variants have distinct cellular and biochemical activities

Mutations in anaplastic lymphoma kinase (ALK) are associated with high-risk neuroblastoma, a childhood cancer arising in trunk neural crest cells. The role of ALK in undifferentiated NC is still unknown; however, the presence of activating mutations in ALK correlates with migratory and invasive cell behaviours in neuroblastoma cell lines. Here, we show the functional consequences of ALK overexpression on neural crest cells, by comparing wildtype ALK (ALKWT) protein to ALK gain-of-function variants ALKF1174L and ALKR1275Q. Elevated ALK activity, independent of mutational status leads to increased migration velocity and loss of directionality, while ALKF1174L overexpression presents additional effects on cytoskeletal protrusions. These results correlate with increased binding of ALKF1174L to GSK3, which has previously been shown to regulate cytoskeletal dynamics in neural crest cells. Further, molecular dynamics simulations of the ALK-GSK3 complex show high flexibility, suggestive of enhanced allosteric regulation. Together, our data show that activating mutations in ALK drive migratory changes in trunk NC cells, potentially mediated by its novel interacting partner GSK3. Significance StatementAnaplastic lymphoma kinase (ALK)-associated neuroblastoma phenotypes arise in the neural crest lineage, but the effects on neural crest cell behaviours are not well-studied. Here, we use primary mouse neural crest cells to study the functional relevance of ALK-activating mutations on cell migration, which we then biochemically link to interactions with GSK3-isoforms. We also directly compare the activities of wild-type ALK with two gain-of-function variants associated with metastatic disease, ALKF1174L and ALKR1275Q, and find that ALKF1174L causes increased cytoskeletal protrusions and GSK3 binding. Our study provides insights into a signalling pathway in neural crest that drives cytoskeletal rearrangements and pathological migration in neuroblastoma.

biochemistry↗

bioRxiv2025

Exploring the mechanisms governing the initiation of plexiform neurofibromas using Prss56Cre,Nf1-KO mouse model at a single-cell resolution

About half of patients with the genetic disease Neurofibromatosis type 1 (NF1) develop benign nerve sheath tumors, called plexiform neurofibromas (pNFs). Despite important advances in understanding the pathogenesis of pNFs, mainly due to the plethora of dedicated mouse models, the mechanisms responsible for the initiation of this process remain poorly understood. Here, we used a Nf1-KO mouse model targeting biallelic loss of Nf1 in boundary cap cells on a wild type and heterozygous Nf1 background to explore the early events driving pNFs development. All mutants develop subcutaneous hyperplastic nerves with some progressing into pNFs from one year of age. We discovered that skin trauma accelerates this process, highlighting the role of inflammation. While skin trauma has no effect on control subcutaneous nerves, in the mutant nerves on a wildtype background, we observed an expansion of mutant Schwann cells expressing a profibrotic program. A similar response was observed in the mutant nerves on a heterozygous background without skin trauma, highlighting the impact of Nf1 heterozygosity in the nerve micro-environment on the development of pNFs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/662123v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@18709d0org.highwire.dtl.DTLVardef@955a59org.highwire.dtl.DTLVardef@15e9bd2org.highwire.dtl.DTLVardef@481d9f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Leukemia aggressiveness is driven by chromatin remodeling and expression changes of core regulators

Mechanisms driving the increase of cell growth in developing leukemia are not fully understood. We focused on epigenomic regulation of this process by analyzing the changes of chromatin marks and gene expression in leukemic cell clones as they progressed towards increased proliferation in a mouse model of acute myeloid leukemia (AML). This progression was characterized by gradual modulation of chromatin states and gene expression across the genome, with a surprising preferential trend of reversing the prior changes associated with the origins of leukemia. Our analyses of this modulation in independently developing clones predicted a small set of potential growth regulators whose transcriptomic and epigenomic progression was consistent between clones and maintained both in vivo and ex vivo. We selected three of these genes as candidates (Irx5 and Plag1 as growth suppressors and Smad1 as a driver) and successfully validated their causal growth effects by overexpression in leukemic cells. Public patient data confirmed expression levels of IRX5 and SMAD1 as markers of AML status and survival, suggesting that multiomic analysis of evolving clones in a mouse model is a valuable predictive approach relevant to human AML.

molecular biology↗

bioRxiv2024

Expanding the genetic toolbox for the obligate human pathogen Streptococcus pyogenes

Genetic tools form the basis for the study of molecular mechanisms. Despite many recent advances in the field of genetic engineering in bacteria, genetic toolsets remain scarce for non-model organisms, such as the obligatory human pathogen Streptococcus pyogenes. In this study, we set out to develop a comprehensive set of plasmids, promoters and reporters for S. pyogenes. We present an expansion to the current genetic toolbox that comprises new replicative and site-specific integrative plasmids. Moreover, we established a collection of constitutive promoters with a wide variety of strengths as well as a set of novel inducible regulatory elements, including a zinc-inducible promoter, an erythromycin-inducible riboswitch and an IPTG-inducible promoter that outperform previously described inducible systems in terms of tightness and inducibility. In addition, we demonstrated the applicability of two codon-optimized fluorescent proteins, mNeongreen and mKate2, as reporters in S. pyogenes. For this, we adapted a novel chemically defined medium called RPMI4Spy. This medium showed a highly reduced autofluorescence compared to other growth media and allowed efficient signal detection in plate reader assays and fluorescence microscopy. Finally, we developed a plasmid-based system for genome engineering in S. pyogenes featuring the counterselection marker pheS*, which improved the generation of scarless gene deletions. This new toolbox simplifies previously laborious genetic manipulation procedures and lays the foundation for new methodologies to study gene functions in S. pyogenes, leading to a better understanding of its virulence mechanisms and physiology.

synthetic biology↗

bioRxiv2023

Loss of Polycomb Repressive Complex 2 function causes asparaginase resistance in T-acute lymphoblastic leukemia through decreased WNT pathway activity

Loss-of-function mutations and deletions in core components of the epigenetic Polycomb Repressive Complex 2 (PRC2) are associated with poor prognosis and treatment resistance in T-acute lymphoblastic leukemia (T-ALL). We leveraged clinical mutational and transcriptional data to identify a functional link between PRC2 alterations and changes in WNT signaling pathway activity in leukemia cells. Computational integration of transcriptomic, proteomic and phosphoproteomic data from an isogenic T-ALL cellular model revealed reduced activity of the WNT-dependent stabilization of proteins (WNT/STOP) pathway in cells lacking core PRC2 factor EZH2. We discovered that PRC2 loss significantly reduced sensitivity to key T-ALL treatment asparaginase, and that this was mechanistically linked to increased cellular ubiquitination levels that bolstered leukemia cell asparagine reserves. We further found that asparaginase resistance in PRC2-depleted leukemic blasts could be mitigated by pharmaceutical proteasome inhibition, thereby providing a novel and clinically tractable means to tackle induction treatment failure in high-risk T-ALL.

cancer biology↗

bioRxiv2022

Spatial regulation of the glycocalyx component Podocalyxin is a switch for pro-metastatic function

The glycocalyx component and sialomucin Podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumour types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for Galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high versus low surface levels occur in parallel subpopulations within cancer cells. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which PODXL promotes invasion and metastasis.

cell biology↗

bioRxiv2020

Selective Vulnerability of Senescent Glioblastoma Cells to Bcl-XL Inhibition

Despite decades of research and numerous basic science advances, there have only marginal gains in improving glioblastoma multiforme survival. Therefore, new ideas and approaches for treating this aggressive disease are essential to drive progress forward. Conventional therapies, such as radiation and Temozolomide (TMZ), function to cause oxidative stress and DNA damage yielding a senescent-like state of replicative arrest in susceptible cells. However, increasing evidence demonstrates malignant cells can escape senescence leading to tumor recurrence. Ablation of non-replicating senescent tumor cells after radiation and chemotherapy may be an avenue to reduce the rates of tumor recurrence. Senolytic agents have been developed that selectively target senescent cells, but it remains unknown whether senolytics might be utilized against senescent-like glioma cells. We employed radiation or TMZ to induce a functionally senescent state in human glioblastoma cells. Viable cells that survive these treatments were then utilized to screen candidate senolytic drugs, to identify those selectively effective at ablating senescent-like cells over naive non-tumor and proliferative cells. Among 10 candidate senolytic drugs evaluated, only Bcl-XL inhibitors demonstrated reproducible senolytic activity in radiated or TMZ-treated glioma across the majority of GBM cell lines evaluated. Conversely, Bcl-2 inhibitors and other established senolytic drugs failed to show any consistent senolytic activity. In agreement with these data, Bcl-XL knockdown selectively reduced the viability of senescent-like GBM cells, whereas knockdown of Bcl-2 or Bcl-W yielded no senolytic effect. These findings demonstrate the potential to harness radiation-induced biology to ablate latent surviving cells and highlight Bcl-XL dependency as a potential vulnerability of surviving GBM cells after exposure to radiation or TMZ.

cancer biology↗

bioRxiv2018

Alexidine dihydrochloride has broad spectrum activities against diverse fungal pathogens

Invasive fungal infections due to Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, constitute a substantial threat to hospitalized, immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices, and emergence of drug-resistant fungi such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms which increases the chance of infection relapses. Here, we screened a small molecule Prestwick Chemical Library, consisting of 1200 FDA approved off-patent drugs, against C. albicans, C. auris and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens, and their ability to kill preformed biofilms. Our studies identified the bis-biguanide Alexidine dihydrochloride (AXD), as a drug with the highest antifungal and anti-biofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mice central venous catheters in vivo, highlighting its potential as a pan-antifungal drug.\n\nImportanceThe prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multi-drug resistant strains such as C. auris. High mortality related to fungal infections point to major limitations of current antifungal therapy, and an unmet need for new antifungal drugs. We screened a library of repurposed FDA approved inhibitors to identify compounds with activities against a diverse range of fungi, in varied phases of growth. The assays identified Alexidine dihydrochloride (AXD) to have pronounced antifungal activity including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro, and prevented biofilm growth in vivo. Thus AXD has the potential to be developed as a pan-antifungal, anti-biofilm drug.

microbiology↗