Biology subjects

Cohen, M.

Publications and source records attributed to Cohen, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Spatially enforced engagement of PD-1⁺ T cells with AXL⁺ cells reprograms the tumor microenvironment and overcomes anti-PD-1 resistance

Background: AXL overexpression promotes tumor-cell plasticity, local immune suppression, and resistance to PD-1 blockade. Conventional anti-AXL and anti-PD-1 antibodies combinations act independently and do not ensure physical proximity between PD-1+ T cells and AXL+ cells within the immunosuppressive tumor microenvironment. Methods: To address this limitation, we developed a non-tandem, tetravalent IgG bispecific antibody designed to simultaneously engage PD-1 and AXL (BiTE-AXL/PD-1). Its antitumor activity was evaluated using in vitro functional assays and humanized and immunocompetent head and neck squamous cell carcinoma (HNSCC) models and compared with the combination of monospecific anti-AXL and anti-PD-1 antibodies. Spatial multiplex imaging was used to characterize treatment-associated changes in the tumor microenvironment of an anti-PD-1-resistant murine model. Results: BiTE-AXL/PD-1 enhanced T-cell activation, promoted AXL-dependent tumor-T-cell conjugation, and increased tumor-cell killing in vitro, outperforming the combination of the two monospecific antibodies. In humanized and immunocompetent HNSCC models, BiTE treatment significantly delayed tumor growth compared with the antibody combination and was well tolerated, with no overt toxicity. Spatial multiplex imaging revealed a shift from a fibroblast-dominated microenvironment characterized by exhausted CD8+ T cells toward dendritic-cell- and CD8+ T-cell-enriched niches associated with antitumor immune activity. Conclusion: BiTE-AXL/PD-1 promotes physical proximity between PD-1+ T cells and AXL+ cells, enhances antitumor immune responses, and remodels the immunosuppressive tumor microenvironment. These findings support PD-1/AXL bispecific targeting as a promising therapeutic strategy to overcome resistance to PD-1 blockade in HNSCC.

cancer biology↗

bioRxiv2025

Decoy Antibodies Block Extracellular HSP70, Prevent Self Signaling and Inhibit Melanoma Cell Survival

Melanoma cells actively secrete melanosomes-large, extracellular vesicles (EVs) enriched with oncogenic factors that reprogram the tumor microenvironment, enhance self-signaling, and promote tumor growth. Despite their abundance and immunogenic potential, humoral responses to melanoma-derived melanosomes remain unexplored. Here, we identify a novel immune surveillance mechanism in which melanosome-elicited decoy antibodies target melanoma-derived melanosomes by binding to the extracellular form of heat shock protein 70 (HSP70), a chaperone broadly implicated in cancer cell survival and stress adaptation. Anti-HSP70 decoy antibodies potently and effector-independently inhibit growth and survival of both murine and human melanoma cells and suppress key transcriptional programs involved in proliferation, cytoskeletal dynamics, and metabolism. In a preclinical B16 melanoma model, prophylactic administration of decoy monoclonal antibodies Mel322-34 and Mel321-35 conferred significant survival benefits of 27% and 48%, respectively. Strikingly, anti-HSP70 antibodies were enriched in the sera of melanoma patients achieving complete responses to immune checkpoint blockade, in contrast to non-responders with progressive disease. Collectively, our findings uncover a novel EV-antibody axis as a promising avenue to block cancer-promoting signaling pathways. Decoy autoantibodies targeting the extracellular form of HSP70 advance the understanding of tumor-intrinsic vulnerability and promote biomarker-driven immunotherapy in melanoma.

immunology↗

bioRxiv2025

Distinct Virome and Bacteriome Profiles of Term and Preterm Placentas from African, Asian and European Women

While the human placental microbiome has been extensively studied, information regarding the virome remains limited. The association between subclinical placental viral infections and spontaneous preterm birth (PTB) is poorly understood. Hence, we examined fresh placenta samples from women in the UK, Bangladesh, and South Africa to elucidate the virome profiles and association with spontaneous PTB. We employed shotgun metagenomics, real-time PCR, and Gram staining, complemented by bioinformatics, to detect both viruses and bacteria in the decidua and chorionic villous tissues. We did not identify any known pathogenic viruses in 236 placental samples, except for one preterm placenta from the Bangladeshi cohort, where human herpesvirus 6 was detected. The majority of the viruses were bacteriophages present at very low abundance and low frequencies across the three cohorts. Lambdavirus lambda was detected in 14% of UK and 11% of Bangladeshi samples but was absent in South African samples. Papiine betaherpesvirus 3 was identified in 62.5% of South African placentas. Punavirus (29.1%) and Streptococcus phages (16.67%) were also prevalent in South African samples. A variety of bacterial species including Moraxella osloensis, Delftia lacustris, Cutibacterium acnes, Escherichia coli and Staphylococcus epidermidis were detected in samples across the three cohorts in variable frequencies but without any notable tissue immune responses. None of the viruses or bacteria exhibited associations with PTB, except D. lacustris, which was significantly more abundant in preterm compared to term placentas in the Bangladeshi cohort. We conclude that the human placenta harbours a virome predominated by bacteriophages and that subclinical viral infection in spontaneous PTB is rare.

microbiology↗

bioRxiv2025

TREM2 macrophages are associated with enhanced response to PD-1 blockade in human hepatocellular carcinoma

Macrophages are known to dampen tumor immunity. However, identifying druggable targets that modulate these cells to improve existing immunotherapies has been limited by a dearth of studies identifying macrophages that associate with pathological response to immune checkpoint blockade. To fulfill this unmet clinical need, we leveraged transcriptional and spatial profiling of specimens collected from a Phase II clinical trial studying neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC). We determined that the intratumoral abundance of TREM2-expressing macrophages and serological levels of soluble TREM2 are elevated in patients who responded to PD-1 blockade, compared to non-responders. We validated these findings in a second HCC cohort and in the IMbrave150 trial. These highlight the robust potential for TREM2 macrophages to predict therapeutic responses of HCC to immunotherapy. Therefore, our study provides a novel basis for the use of TREM2 macrophages to strategize treatment for patients with HCC to maximize therapeutic benefit.

immunology↗

bioRxiv2025

Superior intracellular detection of cytokines, transcription factors, and phosphoproteins by CyTOF compared with fluorescent cytometry

Unraveling biological complexity, whether it be immune subset distribution in infectious disease(s), autoimmunity or tumor heterogeneity, requires technologies capable of single-cell proteomic analysis, such as flow cytometry. Surface immunophenotyping alone is often insufficient, as interrogating functional capacity is required to determine cellular mechanisms and effectively inform diagnostic biomarker discovery, therapeutics and vaccine development. However, large panels with intracellular markers are subject to numerous challenges, including spectral overlap and background cellular autofluorescence, reducing resolving power for rare subsets or populations defined by low-abundance expression. We posited that mass cytometry may overcome such limitations; to address this, three small (11-12-plex) clone-matched antibody panels were evaluated by spectral flow and mass cytometry. Panels were comprised of surface and intracellular targets (phospho-epitopes, transcription factors or cytokines) and designed to minimize fluorescence spectral overlap. CyTOF technology offered superior signal resolution across the range of intracellular targets. Improved signal-to-noise provided better resolution of phospho-events and transcription factor expression, in particular TOX and T-bet. Most strikingly, stimulation-specific IL-10+ and IL-13+ cells were only detected by CyTOF. Superior resolution of these cytokines enabled accurate population clustering, permitting more unique immune cell signatures to be found, including Tr1 and Tc2 populations, thus providing a more comprehensive picture of the immuno-diversity present. Our findings indicate that CyTOF technology could catalyze seminal discoveries in functional immune profiling, driving therapeutic design and diagnostics.

immunology↗

bioRxiv2025

The precision of hippocampal representations predicts incremental value-learning across the adult lifespan

Correctly assigning value to different options and leveraging this information to guide choice is a cornerstone of adaptive decision-making. Reinforcement learning (RL) has provided a computational framework to study this process, and neural signals linked to RL have been identified in the striatum and medial prefrontal cortex. More recently, hippocampal contributions to this kind of value-learning have been proposed, at least under some conditions. Here, we test whether the hippocampus provides a signal of the options identity that aids in credit assignment when learning about several perceptually similar items, and evaluate how this process differs across the lifespan. A sample of 251 younger and older adults, including a subset (n = 76) with simultaneous fMRI, completed an RL task in which they learned the value of four houses through trial-and-error. Older adults showed decreased choice accuracy, accompanied by reduced neural signaling of value at choice but not feedback. Using representational similarity analysis, we found that the precision with which choice options were represented in the posterior hippocampus during choice predicted accurate decisions across age groups. Interestingly, despite previous evidence for neural de-differentiation in older adults, we found no support for a "blurring" of these stimulus representations in older adults. Rather, we observed reduced connectivity between the posterior hippocampus and the medial PFC in older adults, and this connectivity correlated with choice consistency. Taken together, these findings identify a hippocampal contribution to incremental value learning, and that reductions in incremental value learning in older adults are associated with the reduced transfer of information between the hippocampus and mPFC, rather than the precision of the information in the hippocampus itself.

neuroscience↗

bioRxiv2025

ELIP is preferentially expressed in stomatal guard cells and has a role in stomatal opening upon transition to light

Plant early light-induced proteins (ELIPs) are chlorophyll-binding thylakoid membrane proteins commonly believed to function in photoprotection. However, results of studies with mutants or transgenic plants have been contradictory regarding this function, and the mechanistic workings of ELIPs have mostly remained elusive. We studied: (1) ELIP function in tomato (Solanum lycoperiscum) by generation and photosynthetic/physiological characterization of slelip mutants under various light conditions; and (2) ELIP tissue/cell localization by monitoring expression of the Venus yellow fluorescent protein fused to the native SlELIP1 promoter ( pSlELIP1::Venus) in transgenic tomato. Notably, slelip mutants did not display compromised photosynthetic performance and were not more sensitive to photoinhibition compared to parental plants, even following direct sunlight exposure. Surprisingly, pSlELIP1::Venus fusions revealed preferential expression in the leaf epidermis and specifically in stomatal guard cells, with no apparent expression in the mesophyll. No major alterations were observed in leaf gas exchange in slelip mutants at different light conditions. Intriguingly, stomatal conductance was reduced in slelip mutants upon the transition from dark to light. We propose an alternative hypothesis for plant ELIPs as players in the response of guard cells to light, connecting chlorophyll to stomatal function, and presenting a novel research direction for these enigmatic proteins.

plant biology↗

bioRxiv2025

T cell-derived IFN-γ Suppresses T Follicular Helper Cell Differentiation and Antibody Responses during Viral Infections

CD4+ T cells play a critical role in antiviral humoral and cellular immune responses. We have previously reported that subcutaneous lymphocytic choriomeningitis virus (s.c. LCMV) infection is characterized by a stark compartmentalization of CD4+ T cells, leading to strong TH1 polarization but virtually absent T follicular helper (TFH) cells, a key driver of humoral immunity. Here, we investigated the mechanisms responsible for this impaired TFH differentiation. We found that T-bet+ cells induced by s.c. LCMV infection encompass a TH1 subset expressing Granzyme-B (GzmB) and a Tcf-1+ subset that retains the potential for TFH differentiation without expressing mature TFH markers. Interestingly, IFN-{gamma} blockade enables full differentiation of Tcf-1+ cells into TFH, formation of germinal centers and increased antibody production. Of note, the suppression of TFH cells by IFN-{gamma} is not directly mediated through CD4+ T cells but rather involves another cell type, likely dendritic cells (DCs). Our study provides novel insights into the mechanisms directing early CD4+ T cell polarization and affecting humoral responses to viruses, laying a foundation for the development of effective vaccine strategies.

immunology↗

bioRxiv2024

Structure-based mechanistic principles for the paradoxical effects of pathological RET mutations

The RET receptor is a transmembrane protein that belongs to the receptor tyrosine kinase family. RET activates signaling pathways regulating cell growth, differentiation, and survival in diverse tissues that include the thyroid and enteric nervous system. Mutations that reduce RET levels or disrupt function can cause Hirschsprungs disease (HSCR), characterized by abnormal distal colon innervation in the developing embryo. In contrast, mutations that constitutively activate RET can lead to tumorigenesis, most notably in multiple endocrine neoplasia type 2 (MEN2) syndromes usually involving the thyroid. Paradoxically, some RET mutations can both reduce RET activity in enteric ganglia, and increase signaling in other tissues, resulting in patients suffering from both HSCR and MEN2A. Although extensive research has been conducted on RET mutations, the structural and mechanistic bases underlying these paradoxical effects remain unclear. Here, we curated data on 70 positions in RET extracellular domains where point-mutations were associated with HSCR, MEN2A, or both. Taking a structure-based approach, we predict the potential effects of mutations in these positions on RET structure. Our analysis suggests that approximately 90% of positions associated with HSCR can, upon mutation, disrupt intramolecular interactions that stabilize RET tertiary structure: residues buried in the protein core, calcium-binding sites, or residues participating in stabilizing intramolecular electrostatic/covalent bonds. A smaller subset of mutations involves substitutions to/from glycines or prolines in key positions. Only a small minority of HSCR-associated positions affect protein-protein interactions needed for signal activation. On the other hand, our analysis showed that [~]75% of mutations in positions that cause MEN2A lead to an unpaired cysteine that can form an intermolecular disulfide bond between two RET monomers. Other mutations that cause MEN2A are also predicted to enhance RET homodimerization via extracellular domains that are proximal to the membrane. Importantly, substitutions that concurrently destabilizes RET tertiary structure and lead to an unpaired cysteine are predicted to cause the paradoxical co-occurrence of HSCR and MEN2A. Our findings suggest a mechanistic basis for almost all identified pathological mutations in RET and imply that therapeutic strategies for targeting RET activity in HSCR and MEN2A may need to be orthogonal.

bioinformatics↗

bioRxiv2024

Neuronal heterogeneity of normalization strength in a circuit model

The size of a neurons receptive field increases along the visual hierarchy. Neurons in higher-order visual areas integrate information through a canonical computation called normalization, where neurons respond sublinearly to multiple stimuli in the receptive field. Neurons in the visual cortex exhibit highly heterogeneous degrees of normalization. Recent population recordings from visual cortex find that the interactions between neurons, measured by spike count correlations, depend on their normalization strengths. However, the circuit mechanism underlying the heterogeneity of normalization is unclear. In this work, we study normalization in a spiking neuron network model of visual cortex. The model produces a range of neuronal heterogeneity of normalization strength and the heterogeneity is highly correlated with the inhibitory current each neuron receives. Our model reproduces the dependence of spike count correlations on normalization as observed in experimental data, which is explained by the covariance with the inhibitory current. We find that neurons with stronger normalization are more sensitive to contrast differences in images and encode information more efficiently. In addition, networks with more heterogeneity in normalization encode more information about visual stimuli. Together, our model provides a mechanistic explanation of heterogeneous normalization strengths in the visual cortex, and sheds new light on the computational benefits of neuronal heterogeneity.

neuroscience↗

bioRxiv2024

A hierarchical Bayesian interaction model to estimate cell-type-specific methylation quantitative trait loci incorporating priors from cell-sorted bisulfite sequencing data

BackgroundMethylation Quantitative Trait Loci (meQTLs) are chromosomal regions that harbor genetic variants affecting DNA methylation levels. The identification of meQTLs can be accomplished through quantifying the effects of single nucleotide polymorphisms (SNPs) on DNA methylation levels, and these inferred meQTLs can shed light on the complex interplay between the genome and methylome. However, most meQTL studies to date utilize bulk methylation datasets composed of different cell types that may have distinct methylation patterns in each cell type. Current technological challenges hinder the comprehensive collection of large-scale, cell-type-specific (CTS) methylation data, which limits our understanding of CTS methylation regulation. To address this challenge, we propose a hierarchical Bayesian interaction model (HBI) to infer CTS meQTLs from bulk methylation data. ResultsOur HBI method integrates bulk methylations data from a large number of samples and CTS methylation data from a small number of samples to estimate CTS meQTLs. Through simulations, we show that HBI improves the estimation (accuracy and power) of CTS genetic effects on DNA methylation. To systematically characterize genome-wide SNP-methylation level associations in multiple cell types, we apply HBI to bulk methylation data measured in peripheral blood mononuclear cells (PBMC) from a cohort of 431 individuals together with flow-sorted cell-derived methylation sequencing (MC-seq) data measured in isolated white blood cells (CD4+ T-cells, CD8+ T-cells, CD16+ monocytes) for 47 individuals. We demonstrate that HBI can identify CTS meQTLs and improve the functional annotation of SNPs. ConclusionsHBI can incorporate strong and robust signals from MC-seq data to improve the estimation of CTS meQTLs. Applying HBI to link the methylome and genome data helps to identify biologically relevant cell types for complex traits.

genetics↗

bioRxiv2023

Impaired Myofibroblast Proliferation is a Central Feature of Pathologic Post-Natal Alveolar Simplification

Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGF{beta}) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGF{beta} signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGF{beta} signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFb signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.

physiology↗

bioRxiv2023

Pre-existing interferon gamma conditions the lung to mediate early control of SARS-CoV-2

Interferons (IFNs) are critical for anti-viral host defence. Type-1 and type-3 IFNs are typically associated with early control of viral replication and promotion of inflammatory immune responses; however, less is known about the role of IFN{gamma} in anti-viral immunity, particularly in the context of SARS-CoV-2. We have previously observed that lung infection with attenuated bacteria Mycobacterium bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 (SCV2) infection and disease in two mouse models. Assessment of the pulmonary cytokine milieu revealed that iv BCG induces a robust IFN{gamma} response and low levels of IFN{beta}. Here we examined the role of ongoing IFN{gamma} responses due to pre-established bacterial infection on SCV2 disease outcomes in two murine models. We report that IFN{gamma} is required for iv BCG induced reduction in pulmonary viral loads and that this outcome is dependent on IFN{gamma} receptor expression by non-hematopoietic cells. Further analysis revealed that BCG infection promotes the upregulation of interferon-stimulated genes (ISGs) with reported anti-viral activity by pneumocytes and bronchial epithelial cells in an IFN{gamma}-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirmed the importance of IFN{gamma} in these anti-viral effects by demonstrating that the recombinant cytokine itself provides strong protection against SCV2 challenge when administered intranasally. Together, our data show that a pre-established IFN{gamma} response within the lung is protective against SCV2 infection, suggesting that concurrent or recent infections that drive IFN{gamma} may limit the pathogenesis of SCV2 and supporting possible prophylactic uses of IFN{gamma} in COVID-19 management.

immunology↗

bioRxiv2023

A Molecular Communication model for cellular metabolism

Understanding cellular engagement with its environment is essential to control and monitor metabolism. Molecular Communication theory (MC) offers a computational means to identify environmental perturbations that direct or signify cellular behaviors by quantifying the information about a molecular environment that is transmitted through a metabolic system. We developed an model that integrates conventional flux balance analysis metabolic modeling (FBA) and MC to mechanistically expand the scope of MC, and thereby uniquely blends mechanistic biology and information theory to understand how substrate consumption is captured reaction activity, metabolite excretion, and biomass growth. This is enabled by defining several channels through which environmental information transmits in a metabolic network. The information flow in bits that is calculated through this workflow further determines the maximal metabolic effect of environmental perturbations on cellular metabolism and behaviors, since FBA simulates maximal efficiency of the metabolic system. We exemplify this method on two intestinal symbionts - Bacteroides thetaiotaomicron and Methanobrevibacter smithii - and visually consolidated the results into constellation diagrams that facilitate interpretation of information flow from given environments and thereby cultivate the design of controllable biological systems. The unique confluence of metabolic modeling and information theory in this model advances basic understanding of cellular metabolism and has applied value for the Internet of Bio-Nano Things, synthetic biology, microbial ecology, and autonomous laboratories.

bioinformatics↗

bioRxiv2022

Development of Enterovirus anti-viral agents that target the viral 2C protein

The enterovirus (EV) genus includes a number of important human and animal pathogens. EV-A71, EV-D68, poliovirus (PV), and coxsackievirus (CV) outbreaks have affected millions worldwide causing a range of upper respiratory, skin, neuromuscular diseases, including acute flaccid myelitis, and hand-foot-and-mouth disease. There are no FDA-approved anti-viral therapeutics for these enteroviruses. In this study, we describe novel broad spectrum anti-viral compounds targeting the conserved non-structural viral protein 2C that have low micro-molar to nanomolar IC50 values. The selection of resistant mutants resulted in amino acid substitutions in the viral capsid protein, implying a role for 2C in capsid assembly, as has been seen in PV. The assembly and encapsidation stages of the viral life cycle are not fully understood and the inhibitors reported here could be useful probes in understanding these processes.

pharmacology and toxicology↗

bioRxiv2022

Identification and Mechanistic Basis of non-ACE2 Blocking Neutralizing Antibodies from COVID-19 Patients with Deep RNA Sequencing and Molecular Dynamics Simulations

Variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continue to cause disease and impair the effectiveness of treatments. The therapeutic potential of convergent neutralizing antibodies (NAbs) from fully recovered patients has been explored in several early stages of novel drugs. Here, we identified initially elicited NAbs (Ig Heavy, Ig lambda, Ig kappa) in response to COVID-19 infection in patients admitted to the intensive care unit at a single center with deep RNA sequencing (>100 million reads) of peripheral blood as a diagnostic tool for predicting the severity of the disease and as a means to pinpoint specific compensatory NAb treatments. Clinical data were prospectively collected at multiple time points during ICU admission, and amino acid sequences for the NAb CDR3 segments were identified. Patients who survived severe COVID-19 had significantly more of a Class 3 antibody (C135) to SARS-CoV-2 compared to non-survivors (16,315 reads vs 1,412 reads, p=0.02). In addition to highlighting the utility of RNA sequencing in revealing unique NAb profiles in COVID-19 patients with different outcomes, we provided a physical basis for our findings via atomistic modeling combined with molecular dynamics simulations. We established the interactions of the Class 3 NAb C135 with the SARS-CoV-2 spike protein, proposing a mechanistic basis for inhibition via multiple conformations that can effectively prevent ACE2 from binding to the spike protein, despite C135 not directly blocking the ACE2 binding motif. Overall, we demonstrate that deep RNA sequencing combined with structural modeling offers the new potential to identify and understand novel therapeutic(s) NAbs in individuals lacking certain immune responses due to their poor endogenous production. Our results suggest a possible window of opportunity for administration of such NAbs when their full sequence becomes available. A method involving rapid deep RNA sequencing of patients infected with SARS-CoV-2 or its variants at the earliest infection time could help to develop personalized treatments using the identified specific NAbs.

immunology↗

bioRxiv2021

Topological insights into the neural basis of flexible behavior

It is widely accepted that there is an inextricable link between neural computations, biological mechanisms, and behavior, but it is challenging to simultaneously relate all three. Here, we show that topological data analysis (TDA) provides an important bridge between these approaches to studying how brains mediate behavior. We demonstrate that cognitive processes change the topological description of the shared activity of populations of visual neurons. These topological changes constrain and distinguish between competing mechanistic models, are connected to subjects performance on a visual change detection task, and, via a link with network control theory, reveal a tradeoff between improving sensitivity to subtle visual stimulus changes and increasing the chance that the subject will stray off task. These connections provide a blueprint for using TDA to uncover the biological and computational mechanisms by which cognition affects behavior in health and disease. Significance StatementAs the fields of systems, computational, and cognitive neuroscience strive to establish links between computations, biology, and behavior, there is an increasing need for an analysis framework to bridge levels of analysis. We demonstrate that topological data analysis (TDA) of the shared activity of populations of neurons provides that link. TDA allows us to distinguish between competing mechanistic models and to answer longstanding questions in cognitive neuroscience, such as why there is a tradeoff between visual sensitivity and staying on task. These results and analysis framework have applications to many systems within neuroscience and beyond.

neuroscience↗

bioRxiv2021

delilah, prospero and D-Pax2 constitute a gene regulatory network essential for the development of functional proprioceptors

Coordinated animal locomotion depends on the development of functional proprioceptors. While early cell-fate determination processes are well characterized, little is known about the terminal differentiation of cells within the proprioceptive lineage and the genetic networks that control them. In this work we describe a gene regulatory network consisting of three transcription factors-Prospero (Pros), D-Pax2 and Delilah (Dei)-that dictates two alternative differentiation programs within the proprioceptive lineage in Drosophila. We show that D-Pax2 and Pros control the differentiation of cap versus scolopale cells in the chordotonal organ lineage by, respectively, activating and repressing the transcription of dei. Normally, D-Pax2 activates the expression of dei in the cap cell but is unable to do so in the scolopale cell where Pros is co-expressed. We further show that D-Pax2 and Pros exert their effects on dei transcription via a 262 bp chordotonal-specific enhancer in which two D-Pax2- and three Pros-binding sites were identified experimentally. When this enhancer was removed from the fly genome, the cap- and ligament-specific expression of dei was lost, resulting in loss of chordotonal organ functionality and defective larval locomotion. Thus, coordinated larval locomotion depends on the activity of a dei enhancer that integrates both activating and repressive inputs for the generation of a functional proprioceptive organ.

developmental biology↗