Biology subjects

Martino, G.

Publications and source records attributed to Martino, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Combination of indomethacin and temperature produces reliable strobilation in Cassiopea xamachana but batch effects create high variability in ephyra outcomes

Indomethacin and temperature shocks are both widely used to induce ephyra production in Cassiopea polyps, yet the combined effect of these stimuli on strobilation rate, ephyra viability, and polyp survivorship has not been systematically examined. We designed a full factorial experiment crossing five indomethacin concentrations (0, 10, 25, 50, and 75 {micro}M) with four temperature treatments (22, 25, 28, and 31{degrees}C) across three independent experimental trials, exposing a total of 288 individual Cassiopea xamachana polyps for 29 days. Overall, 207 of 288 polyps (71.9%) released at least one ephyra. Temperature was the stronger predictor of strobilation: higher temperatures substantially increased the probability of producing a healthy ephyra (log-odds: +0.327 per {degrees}C; {chi}{superscript 2} p = 6.5 x 10-5), while indomethacin had a smaller but significant positive effect (log-odds: +0.024 per {micro}M; {chi}{superscript 2} p = 0.035). The two stimuli acted independently without significant interaction on healthy ephyra production ({chi}{superscript 2} p = 0.87), although their interaction on total ephyra production (including unhealthy releases) was significant ({chi}{superscript 2} p = 1.0 x 10-9). Notably, low indomethacin concentrations (10 and 25 {micro}M) significantly increased the proportion of unhealthy ephyrae relative to seawater controls (paired t-tests: p = 0.035 and p = 0.006, respectively), while higher concentrations (50-75 {micro}M) did not. Polyp survivorship declined significantly at 28{degrees}C and 31{degrees}C but was unaffected by indomethacin. Trial replicate was the most statistically significant predictor of every outcome measured with the third trial producing near-universal strobilation but zero viable ephyrae, a result of an unidentified perturbation. These results indicate that temperature elevation to 28-31{degrees}C is the most reliable induction strategy for C. xamachana and that low indomethacin concentrations should be avoided when ephyra quality is paramount. We also note that cryptic batch-level variables can overwhelm controlled factors and should be addressed in future experimental designs.

zoology↗

bioRxiv2026

More isn't always better: Too much exoskeleton torque can disrupt balance

Wearable exoskeletons are a promising tool for augmenting balance and reducing fall risk. Recent work suggests that active ankle exoskeletons need to act faster than the human to improve reactive balance control. However, the magnitude of exoskeleton torque that is best for improving reactive balance remains unknown. Drawing from the optimal torque for minimizing metabolic expenditure, we hypothesized that reactive balance would improve with increased exoskeleton torque. Participants wearing bilateral ankle exoskeletons were instructed to maintain standing balance during 15cm backward support-surface perturbations. Three exoskeleton plantarflexion torque conditions were tested: NO (Off), LOW (15Nm), or HIGH (30Nm). LOW torque improved balance performance compared to NO torque (p<0.001), with a 7{+/-}3% decrease in peak center of mass (CoM) displacement. Although HIGH torque caused a 9{+/-}11% decrease in peak CoM displacement compared to NO torque (p=0.12), it was not significant due to high intersubject variability. Whereas LOW torque decreased peak CoM displacement in all (range: -0.2 to -1.6cm), HIGH torque only decreased it in some (range = 1.2 to -2.6cm). The change in CoM displacement from LOW to HIGH torque was associated with balance ability, quantified by the narrowing beam test (R2=0.29, p=0.06), while this relationship didnt meet conventional statistical significance, likely due to the small sample size, it suggests that higher levels of exoskeleton torque may hinder balance performance in individuals with better balance ability. Taken together, more exoskeleton torque is not always better for balance, highlighting a potential need to personalize exoskeleton torque for balance augmentation.

bioengineering↗

bioRxiv2026

Development of a Humanized Mouse Model for Studying adult Spinal Cord myelination, remyelination and Drug Efficacy

Oligodendrocytes are essential for central nervous system (CNS) function through their roles in myelination and neuronal support. Remyelination, the regeneration of myelin after damage, often fails in human demyelinating diseases, leading to progressive neurological dysfunction. While the biology of rodent oligodendroglia has been investigated in depth, species-specific differences have hindered the study of human oligodendrocyte progenitor cells maturation using current animal models. To address this gap, we developed a humanized oligodendroglia chimeric mouse model by transplanting human iPSC-derived O4+ oligodendroglial progenitors (hiOLs) into the developing spinal cord of myelin deficient-immunosuppressed mice followed by demyelination of the adult humanized spinal cord. This paradigm allows in vivo investigation of hiOL fate during their maturation and ageing, and the response of their settled progeny to demyelinating injury. Following transplantation during postnatal development, hiOLs proliferated, migrated, and differentiated into mature oligodendrocytes, initiating axonal myelination. A population of undifferentiated, proliferative adult human oligodendrocyte progenitors presisted, indicating a reservoir of these cells capable of responding to injury. Spinal cord focal demyelination via lysolecithin injection in the adult humanized spinal cord led to transient loss of human-derived mature oligodendrocytes and myelin, followed by myelin recovery together with endogenous cells. Treatment with the histamine receptor H3 antagonist, bavisant, a recently identified promyelinating compound, significantly enhanced hiOL maturation and myelin production, indicating promotion of their differentiation when administered post-demyelination. Electron microscopy showed an increased number of human-derived remyelinated axons together with decreased g-ratios in bavisant treated animals. This humanized spinal cord model of myelination/demyelination-remyelination faithfully recapitulates key aspects of human oligodendrocyte biology and CNS repair, providing a powerful tool to study human-specific myelination and remyelination mechanisms and screen for emerging remyelinating therapies. Its application in disease modeling and preclinical testing holds promise for advancing personalized treatments in demyelinating and neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Integrated metabolomic and metagenomic profiling reveals distinct signatures in treatment naive multiple sclerosis patients.

Imbalances in gut microbiota composition and microbiota-associated metabolites have been linked with several neurological diseases, including multiple sclerosis (MS). However, a comprehensive multi-biofluid approach remains lacking. Most studies on MS include patients already receiving treatment and often neglect to account for sex-related differences, which could serve as potential confounding factors. Moreover, they mostly investigate only stools or plasma metabolomics. In this study, we recruited 18 treatment-naive neuroinflammatory patients at diagnosis and compared them with 20 healthy controls, matched for sex and age. We conducted multi-biofluids metabolomic analysis of urine, stool, serum, and cerebrospinal fluid, complemented by taxonomical and functional profiling of the gut microbiome using shotgun metagenomic sequencing. Our results show that MS patients exhibit distinct microbiome composition and urinary metabolomic profiles compared to healthy controls. Furthermore, neuroinflammation is associated with dysregulation of microbially-produced short-chain fatty acids, their intestinal absorption and systemic bioavailability, as illustrated by the altered plasma levels.

neuroscience↗

bioRxiv2025

Endothelial Cells retain inflammatory memory through chromatin remodeling

Sepsis survivors face a heightened risk of secondary infections and chronic vascular dysfunction despite clinical recovery, yet the underlying mechanisms remain poorly defined. Our study identifies a novel mechanism of endothelial inflammatory memory, wherein transient inflammatory exposure induces durable chromatin remodeling, priming endothelial cells for exaggerated responses to subsequent inflammatory insults. Utilizing a clinically relevant two-hit mouse model, cecal ligation and puncture (CLP) followed by secondary Streptococcus pneumoniae (SP) infection, we reveal persistent transcriptional activation in endothelial cells (ECs), characterized by amplified expression of inflammatory cytokines, adhesion molecules (e.g., ICAM-1), complement factors, and interferon-stimulated genes. Genome-wide ATAC-seq analyses demonstrated stable chromatin accessibility at key inflammatory loci, indicative of epigenetic priming. Mechanistically, we uncovered a critical role for the AP-1 transcription factor JunB in mediating this epigenetic remodeling. JunB knockdown attenuated chromatin accessibility and subsequent transcriptional amplification upon secondary challenge, pinpointing JunB-driven chromatin modifications as central to endothelial reprogramming. Our findings offer mechanistic insights into how transient inflammation creates lasting epigenetic states within the endothelium, highlighting JunB as a potential therapeutic target to mitigate chronic endothelial dysfunction and increased susceptibility to secondary infections post-sepsis.

cell biology↗

bioRxiv2025

Multi-center Translational Trial of Remote Ischemic Conditioning in Acute Ischemic Stroke (TRICS BASIC)

BackgroundBasic science studies have reported remote ischemic conditioning (RIC) as neuroprotective in acute ischemic stroke, while clinical evidence remains conflicting. The TRICS BASIC study investigated the efficacy and safety of RIC in experimental ischemic stroke using a rigorous clinical trial methodology. MethodsMulti-center, multi-species, parallel group, randomized, controlled, preclinical trial of transient femoral artery clipping to induce RIC in female and male rats and mice subjected to transient endovascular occlusion of the middle cerebral artery. Animals were randomized to receive RIC, or sham surgery, after reperfusion. The primary endpoint was good functional outcome at 48 hours, assessed using a composite functional neuroscore. Secondary endpoints was infarct volume at 48 hours and safety, assessed using a standardized health report at 24 and 48 hours. Pre-enrollment harmonization, centralized monitoring, allocation concealment, blinded outcome assessment and intention-to-treat analysis were applied. ResultsThe trial enrolled 164 rodents (82 mice and 82 rats) of both sexes (53% females), across seven laboratories. A greater proportion of RIC-treated rodents achieved a favorable functional outcome compared to controls, at 48 hours post-ischemia (55% versus 36%; OR 2.2, 95% CI [1.23-4.4], p=0.009). RIC was associated with a small reduction in infarct volume (standardized mean difference -0.38, 95% CI [-0.70, -0.05], p=0.024). Health monitoring indicated no major safety concerns, and post-operative analgesia requirements were lower in RIC-treated mice. ConclusionsSurgically-induced RIC provided a modest but evident neuroprotective effect in experimental ischemic stroke, underscoring the potential of this strategy as an adjunctive treatment in stroke care. The findings of the TRICS BASIC study highlighted the importance of multicenter preclinical trials in addressing variability and enhancing translational validity. Registrationregistered at preclinicaltrials.eu, identifier PCTE0000177.

neuroscience↗

bioRxiv2025

Design of novel synthetic promoters to tune gene expression in T cells

Transcriptional control of transgene expression can be linked to dynamic changes in cellular states if this is accompanied by differential expression of transcription factors (TFs). Synthetic promoters (SPs) designed to respond to the desired TFs can provide this regulation with compactness, specificity, and orthogonality. T cells display differentially expressed TFs according to the functional state. In solid tumors, the highly immunosuppressive TME and the chronic exposure to antigens lead to a progression of T cells from a functional to a dysfunctional state known as exhaustion (Tex), in which their power against cancer cells is strongly compromised. Importantly, this transition is accompanied by a marked increase of several TFs, among other factors, that drive targeted genetic programs. Strategies to detect and mitigate Tex are extremely needed. Here, we design SPs that respond to TFs differentially expressed in activated and exhausted T cells to enable new classifiers of the functional/dysfunctional states. We developed a library of over 80 SPs responsive to 7 TFs. The SPs showed broad strength of activation of reporter genes or immunomodulatory molecules in HEK293 and Jurkat T cell lines. Moreover, using a transfer learning strategy we show SPs strength predictability. By combining SPs responding to different TFs, we created Boolean logic gates and implemented a feed-forward design that was previously shown to reduce noise in the OFF-state. Finally, as proof of principle, we demonstrate the dynamic activation of the NR4A2-responsive SP according to the T cell state in primary human CD8+ T cells. Collectively we present a sensing platform that provides a versatile tool to study and monitor the dynamic changes occurring in T cells. In perspective the biosensors coupled to therapeutic genes can be used to reprogram the TME and reinvigorate the T cell anti-tumoral functionality, preventing or reverting the exhausted phenotype. Graphical AbstractCreated with BioRender.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/632034v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@136e147org.highwire.dtl.DTLVardef@22e5org.highwire.dtl.DTLVardef@f2e863org.highwire.dtl.DTLVardef@176c02c_HPS_FORMAT_FIGEXP M_FIG C_FIG

synthetic biology↗

bioRxiv2024

Cortically-mediated muscle responses to balance perturbations increase with perturbation magnitude in older adults with and without Parkinson's disease

We lack a clear understanding of how cortical contributions to balance are altered in aging and Parkinsons disease (PD), which limits development of rehabilitation strategies. Processes like balance control are typically mediated through brainstem circuits, with higher-order circuits becoming engaged as needed. Using reactive balance recovery, we investigated how hierarchical neural mechanisms shape balance- correcting muscle activity across task difficulty in older adults (OAs) with and without PD. We hypothesize that feedback loops involving brainstem and cortical circuits contribute to balance control, and cortical engagement increases with challenge, aging, and PD. We decomposed perturbation-evoked agonist and antagonist muscle activity into hierarchical components based on latency using neuromechanical models consisting of two feedback loops with different delays to reflect different neural conduction and processing times. Agonist muscle activity was decomposed into two components that both increased with balance challenge in both groups. The first component occurred [~]120ms and the second occurred [~]210ms, consistent with the latencies of brainstem and transcortical circuits, respectively. Exploratory comparisons to young adults revealed larger transcortical components in OA and PD groups at lower balance challenge levels, consistent with increased cortical involvement with aging. Antagonist muscle activity included destabilizing and stabilizing components, with the destabilizing component correlating to balance ability in OAs but not in PD. These findings demonstrate that neuromechanical models can identify changes in the hierarchical control of balance without direct brain measurements. Identifying cortical contributions during balance control may complement clinical measures of balance ability to inform balance rehabilitation and assistive devices. NEW & NOTEWORTHYA neuromechanical model can decompose perturbation evoked muscle activity into components attributed to brainstem and higher-order sensorimotor feedback based on latency. In older adults with and without PD contributions from higher-order neural circuits increase with balance challenge and are related to clinical measures of balance ability. Interpreting the neural substrates of motor output for balance may reveal individual differences in the hierarchical control of balance, that could inform rehabilitation.

neuroscience↗

bioRxiv2024

Center of mass states render multi-joint torques throughout standing balance recovery

Successful reactive balance control requires coordinated modulation of hip, knee, and ankle torques. Stabilizing joint torques arise from feedforward neural signals that modulate the musculoskeletal systems intrinsic mechanical properties, namely muscle short-range stiffness, and neural feedback pathways that activate muscles in response to sensory input. Although feedforward and feedback pathways are known to modulate the torque at each joint, the role of each pathway to the balance-correcting response across joints is poorly understood. Since the feedforward and feedback torque responses act at different delays following perturbations to balance, we modified the sensorimotor response model (SRM), previously used to analyze the muscle activation response to perturbations, to consist of parallel feedback loops with different delays. Each loop within the model is driven by the same information, center of mass (CoM) kinematics, but each loop has an independent delay. We evaluated if a parallel loop SRM could decompose the reactive torques into the feedforward and feedback contributions during balance-correcting responses to backward support surface translations at four magnitudes. The SRM accurately reconstructed reactive joint torques at the hip, knee, and ankle, across all perturbation magnitudes (R2>0.84 & VAF>0.83). Moreover, the hip and knee exhibited feedforward and feedback components, while the ankle only exhibited feedback components. The lack of a feedforward component at the ankle may occur because the compliance of the Achilles tendon attenuates muscle short-range stiffness. Our model may provide a framework for evaluating changes in the feedforward and feedback contributions to balance that occur due to aging, injury, or disease. NEWS AND NOTEWORTHYReactive balance control requires coordination of neurally-mediated feedforward and feedback pathways to generate stabilizing joint torques at the hip, knee, and ankle. Using a sensorimotor response model, we decomposed reactive joint torques into feedforward and feedback contributions based on delays relative to center of mass kinematics. Responses across joints were driven by the same signals, but contributions from feedforward versus feedback pathways differed, likely due to differences in musculotendon properties between proximal and distal muscles.

bioengineering↗

bioRxiv2024

Glia-enriched stem-cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis

The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from hiPSC-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from MS patients, organoids properly mimic macroglia-microglia neuro-degenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally-resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support implementing this organoid model for drug screening to halt inflammatory neurodegeneration.

neuroscience↗

bioRxiv2024

Neural precursor cells rescue symptoms of Rett syndrome by activation of the Interferon γ pathway

The beneficial effects of Neural Precursor Cell (NPC) transplantation in several neurological disorders are well established and they are generally mediated by the secretion of immunomodulatory and neurotrophic molecules. We therefore investigated whether Rett syndrome (RTT), that represents the first cause of severe intellectual disability in girls, might benefit from an NPC-based therapy. Using in vitro co-cultures, we demonstrate that, by sensing the pathological context, NPC-secreted factors induce the recovery of morphological and synaptic defects typical of Mecp2 deficient neurons. In vivo, we prove that intracerebral transplantation of NPCs in RTT mice significantly ameliorates neurological functions. To uncover the molecular mechanisms underpinning the mediated benefic effects, we analysed the transcriptional profile of the cerebellum of transplanted animals, disclosing the possible involvement of the Interferon {gamma} (IFN{gamma}) pathway. Accordingly, we report the capacity of IFN{gamma} to rescue synaptic defects, as well as motor and cognitive alterations in Mecp2 deficient models, thereby suggesting this molecular pathway as a potential therapeutic target for RTT.

neuroscience↗

bioRxiv2023

Precise cortical contributions to feedback sensorimotor control during reactive balance

The role of the cortex in shaping automatic whole-body motor behaviors such as walking and balance is poorly understood. Gait and balance are typically mediated through subcortical circuits, with the cortex becoming engaged as needed on an individual basis by task difficulty and complexity. However, we lack a mechanistic understanding of how increased cortical contribution to whole-body movements shapes motor output. Here we use reactive balance recovery as a paradigm to identify relationships between hierarchical control mechanisms and their engagement across balance tasks of increasing difficulty in young adults. We hypothesize that parallel sensorimotor feedback loops engaging subcortical and cortical circuits contribute to balance-correcting muscle activity, and that the involvement of cortical circuits increases with balance challenge. We decomposed balance-correcting muscle activity based on hypothesized subcortically- and cortically-mediated feedback components driven by similar sensory information, but with different loop delays. The initial balance-correcting muscle activity was engaged at all levels of balance difficulty. Its onset latency was consistent with subcortical sensorimotor loops observed in the lower limb. An even later, presumed, cortically-mediated burst of muscle activity became additionally engaged as balance task difficulty increased, at latencies consistent with longer transcortical sensorimotor loops. We further demonstrate that evoked cortical activity in central midline areas measured using electroencephalography (EEG) can be explained by a similar sensory transformation as muscle activity but at a delay consistent with its role in a transcortical loop driving later cortical contributions to balance-correcting muscle activity. These results demonstrate that a neuromechanical model of muscle activity can be used to infer cortical contributions to muscle activity without recording brain activity. Our model may provide a useful framework for evaluating changes in cortical contributions to balance that are associated with falls in older adults and in neurological disorders such as Parkinsons disease.

neuroscience↗

bioRxiv2022

Dual role of brain endothelial Gpr126 in blood-brain barrier development and ischemic stroke

The blood-brain barrier (BBB) acquires unique properties for regulation of the neuronal function during development. The genesis of the BBB coupled with angiogenesis is orchestrated by the Wnt/{beta}-catenin signaling pathway. Aside from the importance of Wnt/{beta}-catenin signaling, the molecular mechanisms that regulate these processes are poorly understood. Here, we identify the brain endothelial adhesion G-protein-coupled receptor Gpr126 as a novel target gene of Wnt/{beta}-catenin signaling that is required for postnatal BBB development, and its expression is detrimental for ischemic stroke in adults. We show that Gpr126 expression is high in mouse brain endothelium during BBB formation, but decreases in the adult. Inactivation of Gpr126 in postnatal endothelial cells results in vessel enlargement and impairs acquisition of the BBB characteristics, such as increased neurovascular permeability, and reduced basement membrane protein deposition and pericyte coverage. Mechanistically, Gpr126 is required during developmental angiogenesis to promote endothelial cell migration, acting via an interaction between Lrp1 and 3{beta}1-integrin, which couples vessel morphogenesis to BBB formation. Interestingly, in adult mice with an established BBB, the lack of Gpr126 expression in acute ischemic stroke is protective and coupled with reduced microglia activation, which contributes to an improved neurological outcome. These data identify Gpr126 as a promising therapeutic target to treat ischemic stroke.

cell biology↗

bioRxiv2022

Brain de novo transcriptome assembly of a toad species showing polymorphic anti-predatory behavior

Understanding the genomic underpinnings of antipredatory behaviors is a hot topic in eco-evolutionary research. Yellow-bellied toad of the genus Bombina are textbook examples of the deimatic display, a time-structured behavior aimed at startling predators. Here, we generated the first de novo brain transcriptome of the Apennine yellow-bellied toad Bombina pachypus, a species showing inter-individual variation in the deimatic display. Through Rna-Seq experiments on a set of individuals showing distinct behavioral phenotypes, we generated 316,329,573 reads, which were assembled and annotated. The high-quality assembly was confirmed by assembly validators and by aligning the contigs against the de novo transcriptome with a mapping percentage higher than 91.0%. The homology annotation with DIAMOND (blastx) led to 77,391 contigs annotated on Nr, Swiss Prot and TrEMBL, whereas the domain and site protein prediction made with InterProScan led to 4747 GO-annotated and 1025 KEGG-annotated contigs. The B. pachypus transcriptome described here will be a valuable resource for further studies on the genomic underpinnings of behavioral variation in amphibians.

evolutionary biology↗

bioRxiv2022

Shock or jump: deimatic behaviour is repeatable and polymorphic in a yellow-bellied toad

Inter-individual variation in antipredatory strategies has long attracted curiosity among scientists. Deimatisms is a complex and time-structured antipredatory strategy consisting in prey suddenly unleashing unexpected defences to frighten predators and stop their attack. Being deimatism traditionally considered as a stereotyped antipredatory response, the inter-individual variation in phenotypic traits related to deimatic displays is almost unexplored. In this study, we employed common garden experiments on 71 yellow-bellied toad Bombina pachypus to investigate the extent and pattern of inter-individual variation in the unken-reflex behaviour, a deimatic display performed by some amphibians. Results show that deimatic displays consistently differ among individuals. Only about half of the individuals reacted to the predation stimuli by exhibiting the display, which varied in responsiveness, duration and intensity. All the investigated descriptors were repeatable (R > 0.50, p < 0.01). Finally, we found significant correlations between the measured parameters, defining two alternative behavioural profiles: individuals quickly doing unken-reflex, with high intensity and long duration of the display, and individuals avoiding unken-reflex but rather escaping. Such dichotomy resembles respectively the proactive and reactive coping styles. Such an unexpected variation in deimatic behaviour raises intriguing questions on the evolutionary processes shaping multiple adaptive responses to predation within populations.

ecology↗

bioRxiv2021

Heparin protects human neural progenitor cells from Zika Virus-induced cell death and preserves their differentiation into mature neural-glia cells

Zika virus (ZIKV) is an arbovirus member of the Flaviviridae family that causes severe congenital brain anomalies in infected fetuses. Human neural progenitor cells (hNPCs) are highly permissive to ZIKV infection, causing inhibition of cell proliferation concomitant with an induction of cell death. We previously demonstrated that pharmaceutical-grade heparin inhibited virus-induced cell death with minor effects on in vitro virus replication in ZIKV-infected hNPCs. Here we show that heparin prevented ZIKV-induced intracellular vacuoles, a signature characteristic of paraptosis, but also inhibited necrosis and apoptosis of hNPCs when grown as neurospheres (NS). Furthermore, heparin preserved the differentiation of both ZIKV-infected human-induced pluripotent stem cells (hiPSC) derived-NPCs and fetus-derived NPCs into neural-glial cells. Collectively, these results highlight the potential neuroprotective effect of heparin that could be re-purposed and exploited to drive the development of novel agents for preventing ZIKV damage.

microbiology↗

bioRxiv2021

CCNE1 amplification is synthetic-lethal with PKMYT1 kinase inhibition

Amplification of the gene encoding cyclin E (CCNE1) is an oncogenic driver in several malignancies and is associated with chemoresistance and poor prognosis. To uncover therapeutic targets for CCNE1-amplified tumors, we undertook genome-scale CRISPR/Cas9-based synthetic lethality screens in cellular models of CCNE1 amplification. Here, we report that increasing CCNE1 dosage engenders a vulnerability to the inhibition of the PKMYT1 kinase, a negative regulator of CDK1. To inhibit PKMYT1, we developed RP-6306, an orally bioavailable and selective inhibitor that shows single-agent activity and durable tumor regressions when combined with gemcitabine in models of CCNE1-amplification. RP-6306 treatment causes unscheduled activation of CDK1 selectively in CCNE1 overexpressing-cells, promoting early mitosis in cells undergoing DNA synthesis. CCNE1 overexpression disrupts CDK1 homeostasis at least in part through an early activation of the FOXM1/MYBL2/MuvB-dependent mitotic transcriptional program. We conclude that PKMYT1 inhibition is a promising therapeutic strategy for CCNE1-amplified cancers.

cancer biology↗

bioRxiv2021

CIP2A is a prime synthetic-lethal target for BRCA-mutated cancers

BRCA1/2-mutated cancer cells must adapt to the genome instability caused by their deficiency in homologous recombination. Identifying and targeting these adaptive mechanisms may provide new therapeutic strategies. Here we present the results of genome-scale CRISPR/Cas9-based synthetic lethality screens in isogenic pairs of BRCA1- and BRCA2-deficient cells that identified the gene encoding CIP2A as essential in a wide range of BRCA1- and BRCA2-mutated cells. Unlike PARP inhibition, CIP2A-deficiency does not cause accumulation of replication-associated DNA lesions that require homologous recombination for their repair. CIP2A is cytoplasmic in interphase but, in mitosis, accumulates at DNA lesions as part of a complex with TOPBP1, a multifunctional genome stability factor. In BRCA-deficient cells, the CIP2A-TOPBP1 complex prevents lethal mis-segregation of acentric chromosomes that arises from impaired DNA synthesis. Finally, physical disruption of the CIP2A-TOPBP1 complex is highly deleterious in BRCA-deficient cells and tumors, indicating that targeting this mitotic chromosome stability process represents an attractive synthetic-lethal therapeutic strategy for BRCA1- and BRCA2-mutated cancers.

cancer biology↗