Biology subjects

Alizadeh, A.

Publications and source records attributed to Alizadeh, A..

10 recordsLinked to original sources

bioRxiv2025

Integration of Multiomic and Multi-phenotypic Data Identifies Biological Pathways Associated with Physical Fitness

Unraveling the complex associations between human phenotypes and molecular pathways can pave the way to improved health and performance, but faces a fundamental challenge: the measurable genes, proteins, and metabolites vastly outnumber the participants in even the largest studies, yielding spurious correlations. To address this imbalance, we have developed a bioinformatic framework and computational approach ("PhenoMol") to discover biological drivers of phenotypic characteristics that integrates all available phenotypic data predictive of outcomes and reduces multi-omic data dimensionality by generating "expression circuits" via graph theory constrained by prior biological knowledge of molecular interactions. We applied PhenoMol to analyze causal patterns and predict elite physical performance in a healthy cohort with deep physiological, physical, behavioral, cognitive, and molecular characterization. PhenoMol outperforms regression models based on equivalent analytic methodologies that do not employ network biology for dimensionality reduction. The PhenoMol software is provided for future studies.

bioinformatics↗

bioRxiv2025

Multidimensional characterization of cellular ecosystems in Hodgkin lymphoma

The tissue architecture of classic Hodgkin Lymphoma (CHL) is unique among cancers and characterized by rare malignant Hodgkin and Reed-Sternberg cells that co-evolve with a complex ecosystem of immune cells in the tumor microenvironment (TME). The lack of a comprehensive systems-level interrogation has hindered the description of disease heterogeneity and clinically relevant molecular subtypes. Here, we employed an integrative, multimodal approach to characterize CHL tumors using malignant cell sequencing, spatial transcriptomics and imaging mass cytometry. We identified four molecular subtypes (CST, CN913, STB, and CN2P), each characterized by distinct clinical features, mutational patterns, malignant cell gene expression profiles, and spatial architecture involving immune cell populations. Functional modeling of CSF2RB mutations, a characteristic feature of the CST subtype, revealed dysregulated oncogenic signaling and unique TME crosstalk. These findings highlight the significance of multi-dimensional profiling in elucidating patterns of molecular alterations that drive immune ecosystems and underlie therapeutically exploitable vulnerabilities.

cancer biology↗

bioRxiv2024

How the layer-dependent ratio of excitatory to inhibitory cells shapes cortical coding in balanced networks

The cerebral cortex exhibits a sophisticated neural architecture across its six layers. Recently, it was found that these layers exhibit different ratios of excitatory to inhibitory (EI) neurons, ranging from 4 to 9. This ratio is a key factor for achieving the often reported balance of excitation and inhibition, a hallmark of cortical computation. Although previous studies have explored various biologically realistic aspects of classical balanced networks, such as the effects of more complex neuronal properties including spike frequency adaptation using adaptive exponential integrate and fire (AdEx) neuron models (1), the temporal evolution of randomly connected balanced networks through second order mean field approximations (2), predictions of nonlinear dynamics across diverse neuron models ranging from integrate and fire to Hodgkin-Huxley formulations, thus bridging population dynamics to neuronal electrophysiology (3), the impact of spatial heterogeneity in balanced networks (4-6), and variations in synaptic timescales (7), the specific effects of differences in excitatory-inhibitory (EI) ratios on layer-specific dynamics and computational properties have, to the best of our knowledge, not yet been addressed. We investigate this question using a sparsely connected network model of excitatory and inhibitory neurons. To keep the network in a physiological range of firing rates, we varied the inhibitory firing threshold or the synaptic strength between excitatory and inhibitory neurons. We find that decreasing the EI ratio allows the network to explore a higher-dimensional space and enhance its capacity to represent complex input. By comparing the empirical EI ratios of layer 2/3 and layer 4 in the rodent barrel cortex, we predict that layer 2/3 has a higher dimensionality and coding capacity than layer 4. Furthermore, our analysis of primary visual cortex data from the Allen Brain Institute corroborates these modeling results, also demonstrating increased dimensionality and coding capabilities of layer 2/3.

neuroscience↗

bioRxiv2024

Interspecies hybridization as a route of accessory chromosome origin in fungal species infecting wild grasses

Many fungal plant pathogens have dynamic genomic architectures that can contribute to rapid evolution and adaptation to new niches. Zymoseptoria tritici, an important fungal pathogen of wheat, has a compartmentalized and rapidly evolving genome. In the genome of the reference isolate Z. tritici IPO323, 8 of the 21 chromosomes are accessory. In spite of the profound impact on genome organization, the origin of accessory chromosomes in Z. tritici is still poorly understood. Combining genomics, transcriptomics and epigenomics, we discovered a new chromosome in Z. tritici isolates infecting wild grasses from the genus Aegilops, and we use this discovery to study the origin of accessory chromosomes. The newly identified chromosome presents similar characteristics to known accessory chromosomes in Zymoseptoria species, including presence-absence variation, low gene expression in vitro and in planta, and enrichment with heterochromatin-associated histone methylation marks (H3K27me3). Interestingly, we found an orthologous chromosome in Zymoseptoria ardabiliae, a closely related fungal species also infecting wild grasses. This ortholog chromosome also presents accessory chromosomes characteristics, but lacks the enrichment of heterochromatin-associated methylation marks. Transcriptomic analyses revealed that the orthologous chromosome in Z. ardabiliae harbors active transposable elements (TEs) congruent with lower signatures of host-genome defense mechanisms against TE expansion and spread (quantified as repeat-induced-point (RIP) mutation signatures). Our findings suggest that the chromosome has been exchanged between Z. tritici and Z. ardabiliae by introgressive hybridization events underlining the relevance of hybridization in the evolution of new accessory chromosomes. We speculate that the regulation of TEs has not yet occurred on this new accessory chromosome in Z. ardabiliae, contributing to its rapid evolution.

evolutionary biology↗

bioRxiv2024

Host specialization defines the emergence of new fungal plant pathogen populations

Host-driven selection can be considered a strong driver of pathogen evolution. To successfully infect, colonize and complete their life cycle, plant pathogens are under constant selective pressures imposed by hosts, leading to genetic adaptation and possibly lineage radiation or speciation. Population and comparative genomics approaches are powerful tools to identify signatures of selection associated with host specialization in pathogen genomes and further allow recapturing population histories. Implementing such approaches, we identified evolutionary signatures of divergent host specialisation in distinct lineages of the fungal pathogen Zymoseptoria tritici, a major disease causing-agent of wheat. Unique collections of Z. tritici were isolated from wild (Aegilops spp.) and domesticated (Triticum aestivum) host grasses in the Middle East and whole-genome sequencing was performed in a selected subset of isolates from each collection. We observed distinct population structure between the two host-diverging pathogens and identified particular genomic features in the Aegilops-infecting isolates that may have shaped their evolutionary history. Phylogenomic analyses revealed that A. cylindrica and A. tauchii -infecting populations of Z. tritici form separate clusters, possibly reflecting incipient speciation driven by divergent host specialization. Using infection experiments, we confirm that Z. tritici isolates collected from Aegilops spp. only infect their respective host species and not T. aestivum. Population genomics analyses and demographic inference furthermore allowed us to detect signatures of recent selection and show that divergence of the wheat-infecting lineage likely coincided with wheat domestication. At last, we confirm a virulence-related role for one candidate effector located in a selective sweep region of the A. cylindrica-infecting pathogen. Taken together, our findings highlight the interplay between agricultural and wild hosts on the evolution of fungal plant pathogens and illustrate host specialization as a possible route of rapid pathogen emergence.

evolutionary biology↗

bioRxiv2024

Emergence of sympatric host-specific lineages of the fungal plant pathogen Zymoseptoria passerinii in natural ecosystems

O_LIThe barley disease Septoria Speckled Leaf Blotch, caused by the fungal pathogen Zymoseptoria passerinii, had its last outbreak in North America in the early 2000s. Although rare in agricultural settings, field sampling of wild grasses in the Middle East revealed the disease persistence in wild barley. C_LIO_LIIdentification of Z. passerinii in distinct wild barley species led us to investigate signatures of host specialization using genomics to address the mode of emergence by host tracking or host range expansion. Furthermore, we applied virulence assays and confocal laser microscopy to evaluate if the disease development differs between wild and domesticated barley. C_LIO_LIWild- and domesticated-host infecting populations have diverged, and phylogenetic relationships support the emergence of sympatric host-specific lineages. Cross-virulence assays showed that Zymoseptoria passerinii from domesticated hosts infect domesticated barley and its wild ancestor, Hordeum spontaneum. However, wild isolates from Iran did not infect domesticated barley. Wild and domesticated pathosystems have similar disease timing and progression, suggesting its persistence in natural ecosystems might be tied to environmental conditions. C_LIO_LIThe study supports that a wide range of hosts can foster the emergence of host-specific lineages in sympatry and provide novel insights into the evolution of understudied fungal pathogens on wild crop relatives. C_LI

evolutionary biology↗

bioRxiv2022

Dynamic Control of Eye-Head Gaze Shifts by a Spiking Neural Network Model of the Superior Colliculus

To reorient gaze (the eye in space) towards a target can be achieved by infinitely many combinations of eye- and head movements. However, behavioral measurements show that the primate gaze-control system selects specific contributions of eye- and head to the saccade, which depend on the initial eye-in-head orientation. Single-unit recordings in the primate superior colliculus (SC) during head-unrestrained gaze shifts have further suggested that cells may encode the instantaneous trajectory of a desired straight gaze path in a feedforward way by the total cumulative number of spikes in the neural population, and that the instantaneous gaze kinematics are determined by the neural firing rates. The recordings also indicated that the latter depended strongly on the initial eye position as well. We recently proposed a conceptual model that accounts for many of the observed properties of eye-head gaze shifts and on the potential role of the SC. Here, we extend and test the model by incorporating a spiking neural network of the SC motor map, the output of which drives the eye-head motor control circuitry by linear cumulative summation of individual spike effects of each recruited SC neuron. We propose a simple neural mechanism on SC cells that explains the modulatory influence of feedback from an initial eye-in-head position signal on their spiking activity. The same signal also determines the onset delay of the head movement with respect to the eye. The downstream eye- and head burst generators were taken to be linear, as our earlier work had suggested that much of the nonlinear kinematics of saccadic eye movements may be due to neural encoding at the collicular level, rather than at the brainstem. We show that the spiking activity of the SC population drives gaze to the intended target location within a dynamic local gaze-velocity feedback circuit that yields realistic eye- and head-movement kinematics and dynamic SC gaze-movement fields.

neuroscience↗

bioRxiv2021

A spiking neural network model of the Superior Colliculus that is robust to changes in the spatial-temporal input

Previous studies have indicated that the location of a large neural population in the Superior Colliculus (SC) motor map specifies the amplitude and direction of the saccadic eye-movement vector, while the saccade trajectory and velocity profile are encoded by the population firing rates. We recently proposed a simple spiking neural network model of the SC motor map, based on linear summation of individual spike effects of each recruited neuron, which accounts for many of the observed properties of SC cells in relation to the ensuing eye movement. However, in the model, the cortical input was kept invariant across different saccades. Electrical microstimulation and reversible lesion studies have demonstrated that the saccade properties are quite robust against large changes in supra-threshold SC activation, but that saccade amplitude and peak eye-velocity systematically decrease at low input strengths. These features are not accounted for by the linear spike-vector summation model. Here we show that the models input projection strengths and intra-collicular lateral connections can be tuned to generate saccades that follow the experimental results. Author statementThe midbrain SC generates fast saccadic eye movements through a large population of cells within a topographically organized motor map, in which the location, spike count and temporal firing patterns of recruited cells determine saccade metrics and kinematics. According to the dynamic ensemble-coding model, each recruited SC cell contributes to the saccade by linear vector summation of all its spike contributions. Our previous spiking neural network model used invariant cortical inputs to the SC cells for all saccades. We here improved the robustness of the model to large spatial-temporal variations in the input patterns, by tuning its top-down and lateral synaptic connections, to generate saccades with properties observed in electrophysiological experiments.

neuroscience↗

bioRxiv2020

Recent loss of the Dim2 cytosine DNA methyltransferase impacts mutation rate and evolution in a fungal plant pathogen

DNA methylation is found throughout all domains of life, yet the extent and function of DNA methylation differ between eukaryotes. Strains of the plant pathogenic fungus Zymoseptoria tritici appeared to lack cytosine DNA methylation (5mC) because gene amplification followed by Repeat-Induced Point mutation (RIP) resulted in the inactivation of the dim2 DNA methyltransferase gene. 5mC is, however, present in closely related sister species. We demonstrate that inactivation of dim2 occurred recently as some Z. tritici isolates carry a functional dim2 gene. Moreover, we show that dim2 inactivation occurred by a different path than previously hypothesized. We mapped the genome-wide distribution of 5mC in strains with and without functional dim2. Presence of functional dim2 correlates with high levels of 5mC in transposable elements (TEs), suggesting a role in genome defense. We identified low levels of 5mC in strains carrying inactive dim2 alleles, suggesting that 5mC is maintained over time, presumably by an active Dnmt5 DNA methyltransferase. Integration of a functional dim2 allele in strains with mutated dim2 restored normal 5mC levels, demonstrating de novo cytosine methylation activity of dim2. To assess the importance of 5mC for genome evolution, we performed an evolution experiment, comparing genomes of strains with high levels of 5mC to genomes of strains lacking dim2. We found that the presence of dim2 alters nucleotide composition by promoting C to T transitions (C[->]T) specifically at CpA (CA) sites during mitosis, likely contributing to TE inactivation. Our results show that 5mC density at TEs is a polymorphic trait in Z. tritici populations that can impact genome evolution. Author SummaryCytosine DNA methylation (5mC) is known to silence transposable elements in fungi and thereby appears to contribute to genome stability. The genomes of plant pathogenic fungi are highly diverse, differing substantially in transposon content and distribution. Here, we show extensive differences of 5mC levels within a single species of an important wheat pathogen. These differences were caused by inactivation of the DNA methyltransferase Dim2 in the majority of studied isolates. Presence of widespread 5mC increased point mutation rates in regions with active or mutated transposable elements during mitosis. The mutation pattern is dependent on the presence of Dim2 and resembles a mitotic version of Repeat-Induced Point mutation (RIP). Thus, loss of 5mC may represent an evolutionary trade-off offering adaptive potential at the cost of transposon control.

genetics↗

bioRxiv2017

DNA copy number gains of TCF4 (E2-2) are associated with poor outcome and the activated B-cell-like subtype of diffuse large B-cell lymphoma

The activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) is characterized by the chronic activation of signaling initiated by immunoglobulin- (IgM). By analyzing DNA copy profiles of 1,000 DLBCLs, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. We show that these alterations target the TCF4 (E2-2) transcription factor, and that over-expression of TCF4 leads to its occupancy on immunoglobulin gene enhancers and increased expression of IgM at the transcript and protein level. The TCF4 gene is one of the top BRD4-regulated genes in DLBCL. Using a BET proteolysis-targeting chimera (PROTAC) we show that TCF4 and IgM expression can be extinguished, and ABC-like DLBCL cells can be killed in vitro and in vivo. This highlights a novel genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.

genomics↗