Biology subjects

Mohammadi, M.

Publications and source records attributed to Mohammadi, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Environmentally-mediated yield effects of vernalization and photoperiod alleles in historic winter wheat trials

In common wheat (Triticum aestivum L.), variation at the Vrn1 and Ppd1 loci changes plant phenology, resulting in differential adaptation useful to breeders. Because the effects of phenology on grain yield are conditional on environmental factors, the incorporation of markers for Vrn1 and Ppd1 alleles into breeding approaches has proven difficult. Historic phenotypic, genotypic, and environmental data can provide insight into the relationship between major phenology alleles and grain yield as mediated by environmental variables. Analyses of eight years of breeding trials (1,038 lines at 219 site-years) determined that weak vrn1 alleles and Ppd1 insensitivity alleles have variable effects. These effects change depending on an environment's winter temperature and latitude, respectively, but the environmentally-driven changes in effect of vrn1 alleles are much more variable than effects of Ppd1 alleles. Mediation analyses showed phenologically-dependent environmental variables are one mechanism through which phenological changes created by vrn1 and Ppd1 variants alter yield across multiple developmental stages. Environmentally-driven relationships between flowering time and yield were modeled to estimate yield allele effects as a function of effects on phenology and environmental variables. Weak winter alleles at vrn1 may play a stabilizing role on yield, due to the correlation of winter conditions that drive larger effects with later-season warm temperatures that penalize later maturity. A better mechanistic understanding of how these loci drive environment-specific yield effects may facilitate utilization of markers for these alleles and improve predictive modeling of yield.

genetics↗

bioRxiv2026

Protein Language Model Decoys for Target Decoy Competition in Proteomics: Quality Assessment and Benchmarks

Large-scale proteomics relies heavily on target-decoy competition for false discovery rate estimation in peptide identification, and the performance of this strategy depends strongly on the design of the decoy database. Classical generators such as reversal and shuffling remain widely used. Here, we introduce the first protein language model-based (PLM) decoy generation for peptide identification and benchmark it against classical strategies. We evaluate these approaches using three complementary quality-control layers: sequence-based separability, search-engine-agnostic spectral-space diagnostics, and end-to-end mass spectrometry benchmarks, including pipelines with rescoring. Across these analyses, PLM-based decoys are harder for sequence-only neural networks to distinguish than most classical generators, suggesting fewer obvious sequence-level artifacts. However, this signal is only weakly informative for search performance. Spectral diagnostics further show that short peptides occupy a particularly crowded target-decoy space and are therefore especially prone to local collisions across all generators. In full search pipelines, reverse decoys remain a strong baseline, and current PLM-based generators do not yet provide a clear overall advantage. We therefore view PLM-based decoys not as universal replacements for reverse decoys, but as tunable tools for benchmarking, diagnostics, stress testing, and future adaptive decoy optimization, with increasing value as search models become more expressive.

bioinformatics↗

bioRxiv2026

Towards automated gating of clinical flow cytometry data

Flow cytometry analysis is widespread practice in cell biology, immunology and hematology. Cell populations of interest are typically identified by consecutively examining the expression levels of antigen marker pairs. Since this manual gating process lacks standardization and is time-consuming, several machine learning (ML) methods for automated gating of flow cytometry data have been proposed in recent years. However, their translation into routine workflows has been limited. To address this, we developed the Python package FLAG-X ("flow cytometry automated gating toolbox"), which supports two novel workflows that integrate manual with ML-based gating, using labeled and unlabeled training data. We selected state-of-the-art ML methods developed for automated gating for inclusion in FLAG-X, based on their gating performance in comparison to manual expert annotations. FLAG-X provides a unified interface for top-performing methods and enables seamless integration with standard software for manual gating by exporting results as FCS files. To demonstrate its practical utility, we applied FLAG-X to representative cases from clinical practice. FLAG-X is available at https://anaconda.org/channels/bioconda/packages/flagx/overview. Author summaryIn our research, we work with flow cytometry data, a common laboratory technique to measure the expression of specific antigens in individual cells of a patient sample. In everyday clinical diagnostics or research, experts use dedicated software tools to "manually" inspect these data and often select a subset of cells for further analysis, e.g. B cells for Lymphoma subtype classification. However, this manual procedure, known as gating, can be time-consuming and is not standardized such that outcomes may vary based on the clinician carrying out the cell selection. Automated, machine learning-based methods developed to mitigate those problems are rarely used in routine clinical work. In this study, we set out to close this gap by developing novel workflows that allow clinicians to more easily integrate (semi-)automated approaches into their existing workflows. To do this, we we developed a software package that brings together top-performing methods, functionality to handle clinical flow cytometry data and is designed to be compatible with with existing tools for manual analysis. We evaluated our workflows and toolbox using realistic clinical scenarios and considered practical requirements for their use. By integrating automation into familiar workflows, we strive to make flow cytometry gating both faster and more consistent to support wider use of computational methods in clinical diagnostics.

bioinformatics↗

bioRxiv2025

Genome-Wide Association study in a US soft winter wheat population reveals novel and known sources of resistance to the Septoria tritici blotch pathogen Zymoseptoria tritici

Key message GWAS of 337 soft winter wheat genotypes from a breeding program in Indiana, USA identified marker-trait associations that likely correspond with existing and novel resistances to Septoria tritici blotch disease. Abstract Septoria tritici blotch (STB), caused by the ascomycete fungus Zymoseptoria tritici, is a major disease of wheat worldwide. To find additional sources of resistance, Genome-Wide Association (GWA) was used to analyze 337 soft winter wheat genotypes from Indiana, USA, by inoculating seedlings with two isolates of Z. tritici in a complete randomized design. Necrosis and pycnidia development were assessed at 14, 18 and 22 days post inoculation, enabling the calculation of area under the disease progress curve (AUDPC) for each parameter. Adjusted necrosis and pycnidia AUDPC scores were compared with 14,341 high-quality SNPs in a GWA analysis using the FarmCPU and GAPIT CMLM models to identify markers associated with the resistance. Significant (p < 0.05) isolate {xi} genotype interactions were identified, confirming that the phenotypic variation was caused by isolate-specific resistance genes. Overall, 12 marker-trait associations (MTAs) were identified with Z. tritici necrosis and pycnidia resistance. All mapped MTAs were isolate and necrosis/pycnidia specific. Distinct MTAs were mapped for necrosis and pycnidia on chromosome 6A, and for pycnidia on chromosomes 1A, 1D, 3B, 4A, 5B, 6A and 7A. MTAs on chromosomes 5B, 4A, 6A, and 1D likely corresponded with the known genes Stb1, Stb7, Stb15 and Stb19, respectively. MTAs on chromosomes 1A, 3B, 4A, 6A and 7A were not associated with previously known Stb genes and may be novel. Candidate genes near the marker locations have been identified for further investigations. The GWAS showed that Indiana soft winter wheat germplasm segregates for novel and known Stb genes and constitutes a valuable breeding resource for Z. tritici resistance.

plant biology↗

bioRxiv2025

Cyclin-dependent kinase 9 inhibitors as oncogene signaling modulators in combination with targeted therapy for the treatment of colorectal cancer

BackgroundColorectal cancer (CRC) is the second deadliest cancer worldwide and new treatment options are urgently needed. Cyclin dependent kinase 9 (CDK9) promotes aberrant RNA transcription in cancer and is a promising target for cancer therapies. MethodsUsing CRC cell lines as well as newly established patient-derived organoid models of CRC, we studied the clinically promising CDK9 inhibitors (AZD4573, BAY1125152/VIP152/enitociclib, and NVP2) to determine their therapeutic potential. We investigated the efficacy and mechanisms of action through cell growth and cytotoxicity assays, RNAseq, immunoblotting, and IHC. ResultsWe found CDK9 inhibitors to be highly potent against CRC, through suppression of proliferation and induction of apoptosis. Our results demonstrated CDK9 inhibitors to be broadly active against a set of CRC models derived from a diverse patient population. Our mechanistic studies showed significant suppression of the Mitogen-active protein kinase (MAPK) signaling pathway due to CDK9 inhibitor treatment, suggesting that CDK9 inhibitor efficacy could be enhanced when combined with MAPK pathway inhibitors. As proof-of-concept, we found that CDK9 inhibitors and MEK inhibitors could be combined to synergistically suppress CRC growth and survival. ConclusionsCDK9 inhibitors show promising activity against patient-derived models of CRC. MAPK signaling is particularly suppressed by CDK9 inhibitors. Combining CDK9 inhibitors and targeted therapy against MAPK signaling pathway may be a viable strategy worthy of further investigation preclinically and clinically. State of translational relevanceNovel therapies for chemotherapy-refractory CRC remain urgently needed. Rapid validation of efficacy in appropriate translational models can provide the necessary rationale to test new therapies in clinical trials. Using newly established patient-derived organoids, we validate the preclinical efficacy of transcriptional CDK9 inhibitors against CRC. This is a therapeutic class that has been scarcely evaluated for efficacy against CRC. We found that CDK9 inhibitors potently inhibit patient-derived organoid models of CRC. Our mechanistic work also reveals that clinically achievable concentrations of CDK9 inhibitor treatment results in suppression of MAPK signaling. As proof-of-concept of the potential actionability of our findings, we demonstrate that CDK9 inhibitors can be combined with MEK inhibitors to synergistically suppress CRC growth. Our study provides new patient-derived CRC models as a resource available to others for therapeutic testing, as well as a roadmap for novel hypotheses about synergistic combination treatments using CDK9 inhibitors.

cancer biology↗

bioRxiv2025

Design and Biological Activity of a Novel Brain Penetrant Urea Compound Against Glioblastoma

Glioblastoma (GBM) remains the most lethal primary brain tumor, largely due to therapy-resistant glioma stem cells (GSCs) and the ability of non-stem cells to dedifferentiate under therapeutic pressure. We developed MXC-017, a novel urea-based compound that crosses the blood-brain-barrier, directly targets GSCs, and prevents radiation-induced GSC formation. Using click chemistry pull-down and mass spectrometry, we identified vimentin as the target of MXC-017, further validated by in silico docking. Global transcriptomic profiling (bulk RNA-seq) and single-cell RNA-seq analyses revealed MXC-017s efficacy with minimal off-target effects, supported by metabolic and kinome assays. Normal cell toxicity was negligible in fibroblasts, microglia, astrocytes, and murine neural progenitors. Maximum tolerated dose was identified and we observed significantly extended median survival in 17 PDOX GBM models when treated with MXC-017 plus radiation, benchmarked against standard-of-care temozolomide. These findings underscore the therapeutic potential of vimentin-targeting agents to overcome radiation resistance and improve outcomes for GBM patients. Statement of SignificanceGlioblastomas distinctive nature and the blood-brain barrier hamper therapies targeting therapy-resistant GSCs. We developed a novel urea-based agent that crosses the barrier, targets GSCs, and prevents radiation-induced GSC formation. With minimal off-target effects, reduced toxicity, and superior survival in PDOX models, it offers potential to improve outcome in GBM.

neuroscience↗

bioRxiv2024

Targeting Innate Immune Signaling in Glioma-Initiating Cells Impairs Self-Renewal and Radiation-Induced Cellular Plasticity

Organisms constantly face environmental stressors that threaten their cellular and genomic integrity. In their response, pathogen-associated molecular patterns (PAMPs) and/or damage-associated molecular patterns (DAMPs) are detected by pattern recognition receptors (PRRs) and trigger the innate immune response. In this study we tested the hypothesis that DAMPs contribute to radiation-induced cellular plasticity in Glioblastoma (GBM). GBM is known to be organized hierarchically with a small number of glioma-initiating cells (GICs) driving treatment resistance and recurrences. Using patient-derived GBM specimens, we employed sphere forming capacity assays and in vitro extreme limiting dilution assays to examine how innate immune receptor signaling impacts the maintenance and self-renewal of GICs. By leveraging an imaging system for putative GICs we determined de novo induction of GICs from non-stem glioma cells. We find that GIC maintenance after irradiation is mediated by cGAS-independent STING signaling, possibly involving signaling through TLR4 and TLR9. Induction of radiation-induced plasticity involves TLR3 signaling, with potential roles for other receptors and processes modulated by MyD88. These findings suggest that targeting innate immune signaling could prevent radiation-induced cellular plasticity for potential therapeutic benefit.

cancer biology↗

bioRxiv2024

Sex and Region-Specific Disruption of Autophagy and Mitophagy in Alzheimer's Disease: Linking Cellular Dysfunction to Cognitive Decline

Macroautophagy and mitophagy are critical processes in Alzheimers disease (AD), yet their links to behavioral outcomes, particularly sex-specific differences, are not fully understood. This study investigates autophagy (LC3B-II, SQSTM1) and mitophagy (BNIP3L, BNIP3, BCL2L13) markers in the cortex and hippocampus of male and female 3xTg-AD mice, using western blotting, transmission electron microscopy (TEM), and behavioral tests (novel object recognition and novel object placement). Significant sex-specific differences emerged: female 3xTg-AD mice exhibited autophagosome accumulation due to impaired degradation in the cortex, while males showed fewer autophagosomes, especially in the hippocampus, without significant degradation changes. TEM analyses demonstrated variations in mitochondrial and mitophagosome numbers correlated with memory outcomes. Females had enhanced mitophagy, with higher BNIP3L and BCL2L13 levels, whereas males showed elevated BNIP3 dimers. Cognitive deficits in females correlated with mitochondrial dysfunction in the cortex, while in males, higher LC3B-II levels associated positively with cognitive performance, suggesting protective autophagy effects. Using machine learning, we predicted mitophagosome and mitochondrial numbers based on behavioral data, pioneering a predictive approach to cellular outcomes in AD. These findings underscore the importance of sex-specific regulation of autophagy and mitophagy in AD and support personalized therapeutic approaches targeting these pathways. Integrating machine learning emphasizes its potential to advance neurodegenerative research. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/621097v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1e50ceeorg.highwire.dtl.DTLVardef@b41ac0org.highwire.dtl.DTLVardef@4863d3org.highwire.dtl.DTLVardef@91b2d0_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical AbstractSex-specific differences in autophagy and mitophagy regulation in Alzheimers disease (AD) are highlighted. Female 3xTg-AD mice show autophagosome accumulation and cognitive deficits, while males exhibit variations in mitophagy markers and behavior.

neuroscience↗

bioRxiv2024

Synthetic Genitourinary Image Synthesis via Generative Adversarial Networks: Enhancing AI Diagnostic Precision

In the realm of computational pathology, the scarcity and restricted diversity of genitourinary (GU) tissue datasets pose significant challenges for training robust diagnostic models. This study explores the potential of Generative Adversarial Networks (GANs) to mitigate these limitations by generating high-quality synthetic images of rare or underrepresented GU tissues. We hypothesized that augmenting the training data of computational pathology models with these GAN-generated images, validated through pathologist evaluation and quantitative similarity measures, would significantly enhance model performance in tasks such as tissue classification, segmentation, and disease detection. To test this hypothesis, we employed a GAN model to produce synthetic images of eight different GU tissues. The quality of these images was rigorously assessed using a Relative Inception Score (RIS) of 17.2 {+/-} 0.15 and a Frechet Inception Distance (FID) that stabilized at 120, metrics that reflect the visual and statistical fidelity of the generated images to real histopathological images. Additionally, the synthetic images received an 80% approval rating from board-certified pathologists, further validating their realism and diagnostic utility. We used an alternative Spatial Heterogeneous Recurrence Quantification Analysis (SHRQA) to assess quality in prostate tissue. This allowed us to make a comparison between original and synthetic data in the context of features, which were further validated by the pathologists evaluation. Future work will focus on implementing a deep learning model to evaluate the performance of the augmented datasets in tasks such as tissue classification, segmentation, and disease detection. This will provide a more comprehensive understanding of the utility of GAN-generated synthetic images in enhancing computational pathology workflows. This study not only confirms the feasibility of using GANs for data augmentation in medical image analysis but also highlights the critical role of synthetic data in addressing the challenges of dataset scarcity and imbalance. Future work will focus on refining the generative models to produce even more diverse and complex tissue representations, potentially transforming the landscape of medical diagnostics with AI-driven solutions. CONSENT FOR PUBLICATIONAll authors have provided their consent for publication.

bioengineering↗

bioRxiv2024

A morphology and secretome map of pyroptosis

Pyroptosis represents one type of Programmed Cell Death (PCD). It is a form of inflammatory cell death that is canonically defined by caspase-1 cleavage and Gasdermin-mediated membrane pore formation. Caspase-1 initiates the inflammatory response (through IL-1{beta} processing), and the N-terminal cleaved fragment of Gasdermin D polymerizes at the cell periphery forming pores to secrete pro-inflammatory markers. Cell morphology also changes in pyroptosis, with nuclear condensation and membrane rupture. However, recent research challenges canon, revealing a more complex secretome and morphological response in pyroptosis, including overlapping molecular characterization with other forms of cell death, such as apoptosis. Here, we take a multimodal, systems biology approach to characterize pyroptosis. We treated human Peripheral Blood Mononuclear Cells (PBMCs) with 36 different combinations of stimuli to induce pyroptosis or apoptosis. We applied both secretome profiling (nELISA) and high-content fluorescence microscopy (Cell Painting). To differentiate apoptotic, pyroptotic and control cells, we used canonical secretome markers and modified our Cell Painting assay to mark the N-terminus of Gasdermin-D. We trained hundreds of machine learning (ML) models to reveal intricate morphology signatures of pyroptosis that implicate changes across many different organelles and predict levels of many pro-inflammatory markers. Overall, our analysis provides a detailed map of pyroptosis which includes overlapping and distinct connections with apoptosis revealed through a mechanistic link between cell morphology and cell secretome.

systems biology↗

bioRxiv2024

Integrative multi-omic analysis identifies genes associated with cuticular wax biogenesis in adult maize leaves

Studying the genetic basis of leaf wax composition and its correlation with leaf cuticular conductance (gc) is crucial for improving crop water-use efficiency. The leaf cuticle, which comprises a cutin matrix and various waxes, functions as an extracellular hydrophobic layer, protecting against water loss upon stomatal closure. To address the limited understanding of genes associated with the natural variation of leaf cuticular waxes and their connection to gc, we conducted statistical genetic analyses using leaf transcriptomic, metabolomic, and physiological data sets collected from a maize (Zea mays L.) panel of [~]300 inbred lines. Through a random forest analysis with 60 cuticular wax traits, it was shown that high molecular weight wax esters play an important role in predicting gc. Integrating results from genome-wide and transcriptome-wide studies (GWAS and TWAS) via a Fishers combined test revealed 231 candidate genes detected by all three association tests. Among these, 11 genes exhibit known or predicted roles in cuticle-related processes. Throughout the genome, multiple hotspots consisting of GWAS signals for several traits from one or more wax classes were discovered, identifying four additional plausible candidate genes and providing insights into the genetic basis of correlated wax traits. Establishing a partially shared genetic architecture, we identified 35 genes for both gc and at least one wax trait, with four considered plausible candidates. Our study uncovered the genetic control of maize leaf waxes, establishing a link between wax composition and gc, with implications for potentially breeding more water-use efficient maize. SIGNIFICANCE STATEMENTWe exploited natural variation in the abundance of maize leaf cuticular waxes to identify genetic determinants of wax composition and its relationship to cuticle function as a barrier against water loss. We identified a set of strongly supported candidate genes with plausible functions in cuticular wax biosynthesis or deposition and added to the evidence for wax esters as the most important wax for water barrier function, offering new tools for modification of cuticle-dependent traits.

genetics↗

bioRxiv2023

Piperidine CD4-mimetic compounds expose vulnerable Env epitopes sensitizing HIV-1-infected cells to ADCC

The ability of HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1 infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engage the gp120 within the Phe43 cavity by targeting the highly-conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the -carboxylic acid group of Asp368, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination HIV-1-infected cells.

immunology↗

bioRxiv2023

Indoline CD4-mimetic Compounds Mediate Potent and Broad HIV-1 Inhibition and Sensitization to Antibody-dependent Cellular Cytotoxicity

Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer [(gp120/gp41)3] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more "open," antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable {pi}-{pi} overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.

microbiology↗

bioRxiv2022

Drought adaptability of different subspecies of tetraploid wheat (Triticum turgidum) under contrasting moisture conditions: association with solvent retention capacity and quality-related traits

Few prior efforts have been made to investigate the genetic potential of different subspecies of Triticum turgidum for drought tolerance and their quality-related traits compared with common wheat (Triticum aestivum) and to identify the association among agronomic, micronutrients, and quality-related traits, especially under climate change conditions. In this research, grain quality, technological properties of flour, and some agronomic traits were studied in 33 wheat genotypes from six different subspecies of Triticum turgidum along with three cultivars of Triticum aestivum in the field, applying a well-watering (WW) and a water stress (WS) environment during two growing seasons. A high degree of variation was observed among genotypes for all evaluated traits, demonstrating that selection for these traits would be successful. Consequences of water stress were manifested as declined DM, TGW, GY, and LASRC; and significantly increased GPC, ZEL, GH, WAF, WSRC, SuSRC, and SCSRC compared to the well-watering condition. The reductions in the unextractable polymeric protein fraction and glutenin-to-gliadin ratio indicated a poorer grain yield quality, despite higher protein content. This study showed that the early-maturing genotypes had higher water absorption and pentosan, and therefore are more suitable for bread baking. In contrast, late-maturing genotypes are ideal for cookie and cracker production. Two subspecies of T. turgidum ssp. durum and T. turgidum ssp. dicoccum with high micronutrient densities and quality-related traits, and T. turgidum ssp. oriental due to having high values of grain protein content can be used to improve the quality of T. aestivum through cross-breeding programs. Based on the association of different traits with SRC values and other quality-related traits and PCA results, contrasting genotypes can be used to develop mapping populations for genome studies of grain quality and functional properties of flour in future studies.

genetics↗

bioRxiv2022

Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling

Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, we show that the protein AuTophaGy 5 (ATG5) functions in neurons to regulate the cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA R1, which sequesters the PKA catalytic subunit and diminishes the cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins mediating AMPAR trafficking. Glutamatergic neurons-confined ATG5 deletion augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.

neuroscience↗

bioRxiv2022

V1 receptive field structure contributes to neuronal response latency

The timing of neuronal responses is considered to be important for information transferring and communication across individual neurons. However, the sources of variabilities in the timing of neuronal responses are not well understood and sometimes over-interpreted. A systematic variability in the response latencies of the primary visual cortex has been reported in presence of drifting grating stimulus. Whereas the response latencies are systematically dependent on stimulus orientation. To understand the underlying mechanism of these systematic latencies, we recorded the neuronal response of the cat visual cortex, area 17, and simulated the response latency of V1 neurons, with two geometric models. We showed that outputs of these two models significantly predict the response latencies of the electrophysiology recording during orientation tasks. The periodic patterns created in the raster plots were dependent on the relative position of the stimulus rotation center and the receptive-field sub-regions. We argue the position of stimulus is contributing to systematic response latencies, dependent on drifting orientation. Therefore, we provide a toolbox based on our geometrical model for determining the exact location of RF sub-regions. Our result indicates that a major source of neuronal variability is the lack of fine-tuning in the task parameters. Considering the simplicity of the orientation selectivity task, we argue fine-tuning of stimulus properties is crucial for deduction of neural variability in higher-order cortical areas and understanding their neural dynamics.

neuroscience↗

bioRxiv2021

Integration of GWAS and TWAS to elucidate the genetic architecture of natural variation for leaf cuticular conductance in maize

The cuticle, a hydrophobic layer of cutin and waxes synthesized by plant epidermal cells, is the major barrier to water loss when stomata are closed. Dissecting the genetic architecture of natural variation for maize leaf cuticular conductance (gc) is important for identifying genes relevant to improving crop productivity in drought-prone environments. To this end, we performed an integrated genome- and transcriptome-wide association study (GWAS/TWAS) to identify candidate genes putatively regulating variation in leaf gc. Of the 22 plausible candidate genes identified, five were predicted to be involved in cuticle precursor biosynthesis and export, two in cell wall modification, nine in intracellular membrane trafficking, and seven in the regulation of cuticle development. A gene encoding an INCREASED SALT TOLERANCE1-LIKE1 (ISTL1) protein putatively involved in intracellular protein and membrane trafficking was identified in GWAS and TWAS as the strongest candidate causal gene. A set of maize nested near-isogenic lines that harbor the ISTL1 genomic region from eight donor parents were evaluated for gc, confirming the association between gc and ISTL1 in a haplotype-based association analysis. The findings of this study provide novel insights into the role of regulatory variants in the development of the maize leaf cuticle, and will ultimately assist breeders to develop drought-tolerant maize for target environments. Sentence summaryWe performed an integrated GWAS/TWAS and identified 22 candidate genes putatively regulating variation in maize leaf gc. The association between gc and the strongest candidate causal gene, ISTL1, was validated with maize nested near-isogenic lines.

genetics↗

bioRxiv2020

Disease Risk Analysis in sea turtles: A baseline study to inform conservation efforts

The impact of a range of different threats has resulted in the listing of six out of seven sea turtle species on the IUCN Red List of endangered species. Disease risk analysis (DRA) tools are designed to provide objective, repeatable and documented assessment of the disease risks for a population and measures to reduce these risks through management options. To the best of our knowledge, DRAs have not previously been published for sea turtles, although disease is reported to contribute to sea turtle population decline. Here, a comprehensive list of health hazards is provided for all seven species of sea turtles. The possible risk these hazards pose to the health of sea turtles were assessed and "One Health" aspects of interacting with sea turtles were also investigated. The risk assessment was undertaken in collaboration with more than 30 experts in the field including veterinarians, microbiologists, social scientists, epidemiologists and stakeholders, in the form of two international workshops and one local workshop. The general finding of the DRA was the distinct lack of knowledge regarding a link between the presence of pathogens and diseases manifestation in sea turtles. A higher rate of disease in immunocompromised individuals was repeatedly reported and a possible link between immunosuppression and environmental contaminants as a result of anthropogenic influences was suggested. Society based conservation initiatives and as a result the cultural and social aspect of interacting with sea turtles appeared to need more attention and research. A risk management workshop was carried out to acquire the insights of local policy makers about management options for the risks relevant to Queensland and the options were evaluated considering their feasibility and effectiveness. The sea turtle DRA presented here, is a structured guide for future risk assessments to be used in specific scenarios such as translocation and head-starting programs.

ecology↗