Biology subjects

Hosseini, A.

Publications and source records attributed to Hosseini, A..

11 recordsLinked to original sources

bioRxiv2026

Inter-Individual Variability in Cycling Biomechanics During Experimentally Induced Movement-Evoked Knee Pain

Knee pain can alter lower-limb loading and contribute to inter-limb asymmetry, affecting movement mechanics and rehabilitation. Although cycling is frequently prescribed during rehabilitation, the effects of pain on bilateral cycling biomechanics remain poorly understood. This study investigated experimentally induced movement-evoked knee pain on bilateral torque and power output, inter-limb asymmetry, and inter-individual motor responses during cycling. Twenty-three healthy adults (14M and 9F) completed an incremental cycling test followed by eight randomized constant-load trials under pain and no-pain conditions at two intensities. A custom closed-loop torque-dependent electrical stimulation system induced movement-evoked knee pain during the downstroke while bilateral biomechanics were recorded. At higher intensities, movement-evoked knee pain reduced torque (p=0.026, d=0.566) and power (p=0.010, d=0.657) production in the painful limb and altered the normalized symmetry index (NSI) for power (p=0.005, d=0.659), and torque (p<0.001, d=0.754). At lower intensity, pain-leg power (p=0.154) and torque (p=0.104) did not differ significantly between conditions, although torque NSI indicated greater reliance on the non-pain leg (p=0.017, d=0.538). Despite these group-level responses, substantial inter-individual variability was observed ranging from pronounced unloading to increased pain-leg contribution. These findings demonstrate that movement-evoked knee pain alters cycling mechanical output toward the non-painful limb, with substantial heterogeneity in individual motor responses.

neuroscience↗

bioRxiv2026

Active control of surface immobilization in the foraging behavior of Paramecium

Paramecium is a common freshwater ciliate, a unicellular swimming eukaryote that feeds on bacteria. Since the discovery that its motility is controlled by action potentials, which earned it the nickname of "swimming neuron", many studies have documented the effect of various stimuli on its behavior, as well as their physiological basis, highlighting the richness of adaptive behavior in this unicellular organism. The logic of its autonomous behavior has received comparably less attention. For example, when Paramecium encounters a surface, it may slide or avoid it by a directional change, triggered by an action potential, or it may immobilize on the surface, a behavior often called thigmotaxis. Here we ask why and how Paramecium immobilizes on surfaces. With long term behavioral tracking, we show that this variable behavior is a component of Paramecium's foraging behavior in the presence of bacteria, where the organism alternates between exploring and stopping on surfaces to feed. This immobilization is physiologically controlled by a calcium influx. Using mutant strains, high speed imaging, particle image velocimetry and hydrodynamics simulation, we further show that surface immobilization occurs by an inhibition of locomotor cilia, while oral cilia continue beating strongly. These findings open the perspective of studying the physiological control of foraging in a unicellular organism, a complex ecologically relevant behavior potentially involving sensory processing, memory, decision making, and motor control.

microbiology↗

bioRxiv2026

Cell cycle control of chromatin creates a therapeutic window for epigenetic therapy in tumors

The relationship between cell cycle length and differentiation competence is well established in developmental biology, particularly in embryonic stem cells, where a short G1 phase maintains pluripotency and G1 lengthening permits lineage commitment. Whether this principle operates in cancer cells, where the cell cycle is deregulated and G1 is frequently shortened, and whether it can be pharmacologically exploited for therapy, has not been tested. Here we show that the duration of G1 is a causal determinant of chromatin state in cancer cells and that extending G1 creates a therapeutic window for epigenetic drugs. Using acute myeloid leukemia (AML) as a model, we demonstrate that low-dose palbociclib, at concentrations well below those required for cytostatic arrest, extends G1 without halting proliferation. This modest prolongation reshapes the histone modification landscape: repressive marks (H3K9me2/3, H4K20me2/3) increase while acetylation decreases, and chromatin accessibility rises broadly in the euchromatic compartment. Naturally slow-cycling AML lines share this epigenetic signature regardless of their oncogenic driver mutations, and pharmacologically extending G1 in fast-cycling cells recapitulates it, establishing G1 length as a causal regulator of the cancer epigenome rather than a passive correlate. To identify epigenetic vulnerabilities created by G1 extension, we performed complementary drug and CRISPR-Cas9 screens in G1-extended AML cells. Both approaches converged on LSD1 (KDM1A): slow-cycling AML cells are intrinsically sensitive to LSD1 inhibition, while fast-cycling cells become sensitive when G1 is prolonged. The combination of low-dose palbociclib and LSD1 inhibition triggers differentiation and significantly prolongs survival in AML xenograft models. p21 (CDKN1A) emerges as the central molecular determinant of this response. In slow-cycling AML cells, p21 is highly expressed and its knockdown abolishes LSD1 inhibitor sensitivity. Structure-function analysis using p21 mutants separates the two known activities of p21: the CDK-inhibitory function (which extends G1) is required for sensitization, whereas the PCNA-binding function is dispensable. Three pharmacological routes converge on the same endpoint, CDK inhibition, G1 extension, and a differentiation-competent chromatin state: direct CDK4/6 inhibition by palbociclib, p21 overexpression, and p21 induction through HDAC or EZH1/2 inhibitors. Palbociclib bypasses the requirement for p21 entirely, confirming that G1 length itself, not p21 as a protein, is the critical variable. Mechanistically, the combination of G1 extension and LSD1 inhibition produces a qualitatively distinct chromatin state rather than an additive one. ATAC-seq reveals thousands of combination-exclusive accessible regions, enriched for footprints of myeloid differentiation transcription factors including SPI1/PU.1, IRF1, and STAT1/2. A double-lock principle governs this remodeling: palbociclib drives the removal of repressive marks (H3K9me3 and H3K27me3), while LSD1 inhibition installs active marks at the newly accessible regions. The ncBAF chromatin remodeling complex, identified in our CRISPR screen and validated by knockout of its essential subunits BRD9 and SMARCD1, is specifically required for this response. Loss of ncBAF abolishes the combination-induced chromatin remodeling and differentiation program but does not affect the initial G1 extension or retinoic acid-induced differentiation, indicating that ncBAF specifically couples cell-cycle modulation to chromatin remodeling rather than acting as a general differentiation factor. The principle generalizes beyond AML. In melanoma, breast cancer, and small-cell lung cancer (SCLC), sensitivity to LSD1 inhibition tracks with p21 expression and cycling speed. Primary melanoma samples stratified by p21 recapitulate the same pattern: p21-high, slow-cycling cells are sensitive; p21-low, fast-cycling cells are resistant but can be sensitized by palbociclib cotreatment. Cisplatin-induced drug-tolerant persister (DTP) cells, which emerge as a slow-cycling, chemo-resistant population and upregulate both p21 and LSD1, become vulnerable to LSD1 inhibition and are eradicated by the combination. In melanoma patient-derived xenograft (PDX) models, p21-high tumors respond to LSD1 inhibitor monotherapy, while p21-low tumors are sensitized by palbociclib cotreatment, with p21 knockdown abolishing the response. Together, these findings establish cell-cycle duration as a tunable regulator of the cancer epigenome and demonstrate that pharmacological G1 extension converts cytostatic CDK4/6 inhibition into an epigenetic sensitization strategy. Both fast-proliferating and slow-cycling tumor compartments (including drug-resistant persisters) can be targeted by matching the epigenomic state to the appropriate combination of cell-cycle modulators and epigenetic drugs. p21 emerges as a candidate biomarker for patient stratification. More broadly, our work repositions the cell cycle from a passive conduit for proliferation signals to an active, druggable regulator of chromatin fate, with implications that extend from cancer therapy to stem cell biology and regenerative medicine.

cancer biology↗

bioRxiv2025

Growth-promoting rhizobacteria amend the defense of strawberry plants against sequentially attacking herbivores

Plant defense systems such as induced resistance (IR; induced by herbivores) and induced systemic resistance (ISR; induced by beneficial rhizobacteria) are modulated by the same signaling pathways within plants and hence interact. ISR allows enhanced protection of aboveground plant parts against herbivores before IR induction. Both ISR and IR are systemic and may involve the production of toxic, antifeedant and/or repellent compounds, and/or reduce nutrient availability, which may in consequence affect plant usability and palatability for later arriving herbivores. The combined effects of ISR and IR on different herbivores sharing the same plant and plant performance have been rarely addressed. Here, we assessed the effects of three plant-growth-promoting rhizobacteria (PGPR), Azotobacter chroococcum, Azospirillum brasilense and Pseudomonas brassicacearum, on the defense response and physiology of strawberry plants upon sequential attack by two herbivores with different feeding modes, two-spotted spider mites Tetranychus urticae and cotton aphids Aphis gossypii. Attack of strawberry plants by spider mites and aphids adversely affected the abundance of the later arriving herbivore, mediated by the host plants defense system. First-attacking spider mites exerted much stronger adverse effects on later attacking aphids than first-attacking aphids on later attacking spider mites. In absence of PGPR inoculation, the herbivores, especially first-attacking spider mites, severely impaired host plant physiology and productivity. PGPR inoculation primed the plants defense system to attack by spider mites and aphids, allowing the plants to produce more secondary metabolites such as phenols. In consequence, the abundances of both herbivores were lower on PGPR-inoculated plants compared to chemically fertilized and control plants. Overall, our study suggests that PGPR inoculation ameliorates the plant damage caused by sequentially attacking herbivores. Additionally, the PGPRs improve the physiology and productivity, and favorably balance the nutritional state, of strawberry plants.

ecology↗

bioRxiv2025

Somatostatin Receptors Shape Insulin and Glucagon Output within the Pancreatic Islet through Direct and Paracrine Effects

Aims/HypothesisPancreatic delta cells secrete somatostatin (SST), which can inhibit both alpha and beta cells of the pancreatic islet. By controlling insulin and glucagon release, delta cells play an important role in maintaining nutrient homeostasis. However, the mechanism by which a single inhibitory hormone inhibits both alpha and beta cells, which are often considered as functional antagonists in the counterregulatory control of blood glucose, has been a physiological riddle. Here, we solve this riddle through assessment of the contributions of alpha and beta cell specific somatostatin receptors to cell intrinsic behaviors and hormone release. MethodsIslets from mice constitutively expressing fluorescent sensors reporting on cyclic AMP and Ca2+ in both alpha and beta cells were imaged using stimuli to mimic the post-prandial state of a meal consisting of glucose and amino acids. This approach was coupled with cell specific somatostatin receptor antagonists to identify how somatostatin inhibits alpha and beta cell hormone output through modulation of cAMP and Ca2+ secondary messengers and paracrine interactions. ResultsOur results support and extend prior observation that somatostatin receptor 2 (SSTR2) is the only somatostatin receptor expressed by alpha cells, while somatostatin receptor 3 (SSTR3) is the only receptor expressed by mouse beta cells. Interestingly, SSTR2 and SSTR3 regulate downstream cAMP and Ca2+ signaling cascades differently within alpha and beta cells of intact islets. Stimulation of somatostatin receptors robustly inhibits cyclic AMP in alpha or beta cells. In contrast, stimulation of SSTR2 inhibits alpha cell Ca2+ with significantly greater potency compared to inhibition of beta cell Ca2+ via SSTR3. Despite the absence of SSTR2 on beta cells, blocking alpha cell SSTR2 during nutrient stimulation resulted in a significant increase in insulin release downstream of local release of glucagon. Conclusions/InterpretationOur observations address the physiological riddle of the delta cells role during the post-prandial phase where we demonstrate that somatostatin primarily inhibits alpha cell cAMP and Ca2+ via SSTR2, preventing glucagon release. Blocking SSTR2 resulted in an increase in locally released glucagon, which coupled with muted ability for SSTR3 to inhibit beta cell calcium under strong nutrient stimulation, results in potentiation of glucose stimulated insulin secretion from the beta cell. We conclude that the role of delta cells under nutrient stimulation is to modulate the volume of insulin release by tuning the strength of intra-islet paracrine potentiation of insulin secretion by glucagon, mediated via beta cell GLP1R. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LISomatostatin released by delta cells can attenuate glucagon release from the alpha cells and insulin release from the beta cells of the islet through inhibitory somatostatin receptors. C_LIO_LISomatostatin receptor 2 is a major receptor expressed on the mouse alpha cell surface, while mouse beta cells express SSTR3 on their primary cilia. C_LIO_LIParacrine signaling by alpha cell glucagon potentiates insulin release through the engagement of stimulatory glucagon-like peptide 1 receptors on beta cells. C_LI What are the key questions?O_LIHow do the cell specific somatostatin receptors of the alpha cell (SSTR2) and beta cell (SSTR3) differentially regulate cell-intrinsic Ca2+ and cAMP signaling and the indirect paracrine pathways that shape insulin secretion in the post-prandial state? C_LI What are the new findings?O_LIAlpha cells of the mouse islet express exclusively SSTR2 and not SSTR3. C_LIO_LISomatostatin is a more potent inhibitor of cytosolic calcium activity via alpha cell SSTR2 compared to beta cell SSTR3. C_LIO_LIPreventing somatostatin inhibition of the alpha cell in the presence of elevated glucose and amino acids potentiates insulin release through the engagement of glucagon-like peptide 1 receptors on the beta cell by glucagon. C_LI How might this impact on clinical practice in the foreseeable future?O_LIOur findings indicate that local feedback inhibition of beta cells is accomplished by tuning the strength of the paracrine potentiation of locally released glucagon. This is relevant in the context of developing treatments for hypoglycemia with alpha cell specific SSTR2-specific antagonists that could potentiate insulin release and potentially exacerbate hypoglycemic episodes. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/688371v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1138ddaorg.highwire.dtl.DTLVardef@c613f9org.highwire.dtl.DTLVardef@49806eorg.highwire.dtl.DTLVardef@18ece86_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Mitochondrial Dysfunction Rewires Macrophage Metabolism, Driving Pro-inflammatory Priming and Immune System Remodeling

Macrophage activation is tightly coupled to cellular metabolism: classically activated pro-inflammatory (M1) macrophages rely on glycolysis and a disrupted tricarboxylic acid cycle, whereas alternatively activated (M2) macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation. Although mitochondria are central to this metabolic plasticity, it remains unclear whether mitochondrial dysfunction itself can dictate macrophage polarization. Using macrophage-specific OPA1 knockout mice, we investigated how mitochondrial dysfunction influences macrophage metabolism and immune homeostasis. Loss of OPA1 caused severe impairment of OXPHOS, reduced mitochondrial membrane potential, and a compensatory glycolytic shift, driving M0 and M2 macrophages toward an M1-like bioenergetic state. Integrative metabolomic and transcriptomic analyses revealed strong priming of OPA1-deficient macrophages towards classical activation, including accumulation of M1-associated metabolites (lactate, succinate, itaconate) and upregulation of NF-{kappa}B-driven and other inflammatory gene programs, resulting in increased secretion of IL-6 and TNF even in the absence of stimulation. Functionally, this metabolic shift primed non-activated and M2 macrophages toward partial M1 polarization with enhanced bactericidal capacity, while simultaneously suppressing M2-associated processes such as proliferation, efferocytosis, and expression of Arg1, CD206, and RELM. In vivo, OPA1{Delta}M mice displayed reduced peritoneal macrophage abundance, impaired self-renewal after IL-4 complex stimulation, and compensatory monocyte recruitment. The remaining macrophages exhibited increased MHCII and reduced RELM expression, consistent with partial M1 skewing and loss of alternative activation. These local alterations were mirrored systemically: blood profiling revealed enhanced T-cell activation and sex-specific remodeling of immune composition during inflammation and aging. Collectively, these findings demonstrate that mitochondrial dysfunction serves as a cell-intrinsic cue that primes macrophages toward a glycolytic, pro-inflammatory phenotype while constraining their M2 properties and proliferative capacities. This dual metabolic and functional rewiring highlights mitochondrial integrity as a pivotal determinant of macrophage immunometabolic identity and reveals how its disruption can reshape both local and systemic immune homeostasis.

immunology↗

bioRxiv2025

Single camera estimation of microswimmer depth with a convolutional network

A number of techniques have been developed to measure the three-dimensional trajectories of protists, which require special experimental setups, such as a pair of orthogonal cameras. On the other hand, machine learning techniques have been used to estimate the vertical position of spherical particles from the defocus pattern, but they require the acquisition of a labeled dataset with finely spaced vertical positions. Here we describe a simple way to make a dataset of Paramecium images labeled with vertical position from a single 5 minutes movie, based on a tilted slide setup. We used this dataset to train a simple convolutional network to estimate the vertical position of Paramecium from conventional bright field images. As an application, we show that this technique has sufficient accuracy to study the surface following behavior of Paramecium (thigmotaxis).

microbiology↗

bioRxiv2024

APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids

Apolipoprotein E4 (APOE4) is the leading genetic risk factor for Alzheimers disease. While most studies examine the role of APOE4 in aging, imaging, and cognitive assessments reveal that APOE4 influences brain structure and function as early as infancy. Here, we examined human-relevant cellular phenotypes across neurodevelopment using induced pluripotent stem cell (iPSC) derived cortical and ganglionic eminence organoids (COs and GEOs). In COs, we showed that APOE4 decreased BRN2+ and SATB2+ cortical neurons, increased astrocytes and outer radial glia, and was associated with increased cell death and dysregulated GABA-related gene expression. In GEOs, APOE4 accelerated maturation of neural progenitors and neurons. Multi-electrode array recordings in assembloids revealed that APOE4 disrupted network formation and altered response to GABA, resulting in heightened excitability and synchronicity. Together, our data provides new insights into how APOE4 may influence cortical neurodevelopmental processes and network formation in the human brain.

neuroscience↗

bioRxiv2024

Dual effects of ARX poly-alanine mutations in human cortical and interneuron development

Infantile spasms, with an incidence of 1.6 to 4.5 per 10,000 live births, are a relentless and devastating childhood epilepsy marked by severe seizures but also leads to lifelong intellectual disability. Alarmingly, up to 5% of males with this condition carry a mutation in the Aristaless-related homeobox (ARX) gene. Our current lack of human-specific models for developmental epilepsy, coupled with discrepancies between animal studies and human data, underscores the gap in knowledge and urgent need for innovative human models, organoids being one of the best available. Here, we used human neural organoid models, cortical organoids (CO) and ganglionic eminences organoids (GEO) which mimic cortical and interneuron development respectively, to study the consequences of PAE mutations, one of the most prevalent mutation in ARX. ARXPAE produces a decrease expression of ARX in GEOs, and an enhancement in interneuron migration. That accelerated migration is cell autonomously driven, and it can be rescued by inhibiting CXCR4. We also found that PAE mutations result in an early increase in radial glia cells and intermediate progenitor cells, followed by a subsequent loss of cortical neurons at later timepoints. Moreover, ARX expression is upregulated in COs derived from patients at 30 DIV and is associated with alterations in the expression of CDKN1C. Furthermore, ARXPAE assembloids had hyperactivity which were evident at early stages of development. With effective treatments for infantile spasms and developmental epilepsies still elusive, delving into the role of ARXPAE mutations in human brain organoids represents a pivotal step toward uncovering groundbreaking therapeutic strategies.

neuroscience↗

bioRxiv2023

Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer

Viral mimicry describes the immune response induced by endogenous stimuli such as dsRNA formed by endogenous retroelements. Activation of viral mimicry has the potential to kill cancer cells or augment anti-tumor immune response. Paradoxically, cancer cells frequently present a dysregulated epigenome, leading to increased expression of retroelements. We previously found that ADAR1 p150 upregulation is an adaptation mechanism to tolerate high retroelement-derived dsRNA levels, leading to a druggable dependency. Here, we systematically identified novel mechanisms of viral mimicry adaptation associated with cancer cell dependencies. We correlated the gene knockout sensitivity from the DepMap dataset and interferon stimulated gene (ISG) expression in the Cancer Cell Line Encyclopedia (CCLE) dataset of 1005 human cell lines and identified pathways such as RNA modification and nucleic acid metabolism. Among the top hits was the RNA decay protein XRN1 as an essential gene for the survival of a subset of cancer cell lines. XRN1-sensitive cancer cell lines have a high level of cytosolic dsRNA and high ISG expression. Furthermore, sensitivity to XRN1 knockout was mediated by MAVS and PKR activation, indicating that the cells die due to XRN1-dependent induction of viral mimicry. XRN1-resistant cell lines had low basal dsRNA levels, but became synthetically dependent on XRN1 upon treatment with viral mimicry inducing drugs such as 5-AZA-CdR or palbociclib. Finally, XRN1-dependency is partly independent of ADAR1 activity. These results confirm the potential for our ISG correlation analysis to discover novel regulators of viral mimicry and show that XRN1 activation is an adaptive mechanism to control high dsRNA stress induced by dysregulated retroelements in cancer cells and creates a dependency that can be explored for novel cancer therapies.

cell biology↗

bioRxiv2018

Predicting the effects of epidural stimulation to improve hand function in patients with spinal cord injury: An active learning-based solution using dynamic sample weighting

In patients with chronic spinal cord injury (SCI), few therapies are available to improve neurological function. Neuromodulation of the spinal cord with epidural stimulation (EDS) has shown promise enabling the voluntary activation of motor pools caudal to the level of the injury. EDS is performed with multiple electrode arrays in which several stimulation variables such as the frequency, amplitude, and location of the stimulation significantly affect the type and amplitude of motor responses. This paper presents a novel technique to predict the final functionality of a patient with SCI after cervical EDS within a deep learning framework. Additionally, we suggest a committee-based active learning method to reduce the number of clinical experiments required to optimize EDS stimulation variables by exploring the stimulation configuration space more efficiently. We also developed a novel method to dynamically weight the results of different experiments using neural networks to create an optimal estimate of the quantity of interest. The essence of our approach was to use machine learning methods to predict the hand contraction force in a patient with chronic SCI based on different EDS parameters. The accuracy of the prediction of stimulation outcomes was evaluated based on three measurements: mean absolute error, standard deviation, and correlation coefficient. The results show that the proposed method can be used to reliably predict the outcome of cervical EDS on maximum voluntary contraction force of the hand with a prediction error of approximately 15%. This model could allow scientists to establish stimulation parameters more efficiently for SCI patients to produce enhanced motor responses in this novel application.\n\nAuthor SummarySpinal cord injury (SCI) can lead to permanent sensorimotor deficits that have a major impact on quality of life. In patients with a motor complete injury, there is no therapy available to reliably improve motor function. Recently, neuromodulation of the spinal cord with epidural stimulation (EDS) has allowed patients with motor-complete SCI regain voluntary movement below the level of injury in the cervical and thoracic spine. EDS is performed using multi-electrode arrays placed in the dorsal epidural space spanning several spinal segments. There are numerous stimulation parameters that can be modified to produce different effects on motor function. Previously, defining these parameters was based on observation and empiric testing, which are time-consuming and inefficient processes. There is a need for an automated method to predict motor and sensory function based on a given combination of EDS settings. We developed a novel method to predict the gripping function of a patient with SCI undergoing cervical EDS based on a set of stimulation parameters within a deep learning framework. We also addressed a limiting factor in machine learning methods in EDS, which is a general lack of training measurements for the learning model. We proposed a novel active learning method to minimize the number of training measurements required. The model for predicting responses to EDS could be used by scientists and clinicians to efficiently determine a set of stimulation parameters that produce a desired effect on motor function.

neuroscience↗