Biology subjects

Israel, S.

Publications and source records attributed to Israel, S..

12 recordsLinked to original sources

bioRxiv2026

Internet-delivered cognitive behavioral therapy is associated with distinct blood small RNA profiles in panic disorder

Panic disorder associates with altered fear circuitry, autonomic dysregulation and stress-related immune perturbations, yet its molecular and treatment-response signatures remain poorly defined. Internet-delivered cognitive behavioral therapy (iCBT) is an effective first-line treatment with unexplained outcome variations across individuals. Here, we report altered profiles of small non-coding RNAs in peripheral blood mononuclear cells from panic disorder patients before and after iCBT, compared with longitudinally sampled healthy controls. Thirteen top-ranking microRNAs discriminated patients from controls and separated pre- and post-treatment states, both of which differed from controls. Correspondingly, baseline hsa-miR-125b-5p levels were significantly associated with post-iCBT symptom improvement. Transfer RNA-derived fragments (tRFs) showed even greater discriminatory power, with nuclear-Val-3'-tRF family members exhibiting a pronounced post-treatment shift. Pathway analyses of panic disorder-associated and CBT-responsive small RNA targets converged on immune-related pathways, supporting a role in inflammatory mechanisms and highlighting blood small non-coding RNAs as promising biomarkers of panic disorder and its therapeutic response.

molecular biology↗

bioRxiv2025

A novel and critical role of the intracellular Zona Pellucida protein 2 (ZP2) for blastocyst formation in mice

The zona pellucida (ZP) is the quintessential extracellular structure of mammalian oocytes. Contrary to long-standing view that the synthesis of ZP proteins is specific to oocytes and muted in embryos, we report here that the major zona pellucida protein ZP2 is re-synthesized and functionally required during mouse embryo development. The orthogonal methods of mass spectrometry and monoclonal immunofluorescence revealed an increase of ZP2 abundance at the 8-cell / morula stage, which did not occur when zygotes were microinjected with translation-blocking oligonucleotides (morpholinos). To shed light on the functional significance of embryonic ZP2, we performed protein knockdown using immunodepletion (by Trim-Away) while at the same time preventing replenishment (by translation-blocking morpholino). ZP2 knockdown resulted in morula stage retardation and formation of defective blastocysts, whose cell lineages trophectoderm and primitive endoderm were smaller and less able to support post-implantation development. The transcriptional correlates of these morphological alterations had a gene ontology (biological process) signature that included cell lineage-relevant terms ( endoderm development, gastrulation), while the proteomic correlates had a gene ontology signature related to protein synthesis. Taken together, these results call into question the traditional model that ZP proteins function solely in the extracellular space and accompany embryogenesis as passive bystanders: on the contrary, ZP proteins also participate actively in the intracellular processes of early embryogenesis.

developmental biology↗

bioRxiv2025

IMMUNOGENICITY AND SAFETY OF CHICKEN EMBRYO FIBROBLAST ADAPTED FOWLPOX VACCINE

BackgroundThe use of chorioallantoic membranes (CAM) route for the propagation of fowlpox virus (FPV) is the method applied in the production of potent and effective fowlpox vaccine at the National Veterinary Research Institute (NVRI), Vom. However, production insufficiency has led to inadequate supply of vaccine to meet farmers demands. This has left large number of susceptible and unvaccinated flocks with outbreaks of the disease being reported in Nigerian. AimThis study adapted FPV to Chicken embryo fibroblast (CEF) cell culture and assessed its immunogenicity and safety of the resulting vaccine in comparison to a locally produced CAM-based FPV vaccine. MethodsThe FPV were propagated on CAM and CEF of 9 to 12 day old developing chicken embryos. The vaccine harvests were subjected to quality checks, titrated, and used in vaccinating experimental birds via the wing web to monitor for takes, seroconversion, and safety. ResultsThe FPV was successful adapted to CEF as demonstrated by the attainment of 80 to 90% cytopathic effect within 71 to 115 hours in the different passages. Both the CEF and CAM-adapted vaccine harvests were highly replicative producing titres of above 106.0/ml TCID50, but higher titres of 108.25/ml TCID50 was recorded in the CEF-adapted vaccines. Experimentally vaccinated birds showed 100% takes within 3 to 4 days post-vaccination, with no adverse effects recorded. ConclusionThis research reported successful development and adaptation of FPV to CEF that was safe and immunogenic, with the potential for its use in the production of self-sufficiency vaccine for fowlpox prevention and control in poultry.

immunology↗

bioRxiv2023

First cleavage is a manifestation of the geometry of the unfertilized oocyte: implications for monozygotic twinning in mice.

A long-standing question in mammalian embryology is whether regional differences of oocyte composition matter for the properties of blastomeres receiving those regions after fertilization. A hitherto untested hypothesis is that allocation depends on the orientation of 1st cleavage. However, the orientation is influenced by the site of sperm entry, which can be almost anywhere on the membrane of oocytes when these are inseminated. This variability undermines consistency and reproducibility of studies. Therefore, we harnessed the intracytoplasmic sperm injection to impose the site of fertilization in three specific ooplasmic regions (animal pole, vegetal pole, equator) in mice. Notwithstanding this categorical distinction, after 1st cleavage, the sister blastomeres differed from each other nearly the same way, as measured by gene expression and twin blastocysts formation following 2-cell embryo splitting. We reasoned that either the oocyte territories did not matter, or their effect was obscured by other factors. To shed light on these possibilities, we immobilized the oocytes on the micromanipulation stage during sperm injection and for 24 h thereafter. Imaging revealed that the orientation of 1st cleavage, instead of varying with the fertilization site, followed the shorter diameter of the unfertilized oocyte. This led in most cases to the segregation of animal and vegetal hemispheres into the sister blastomeres of 2-cell embryos. Since one blastomere received more of the animal materials and the other blastomere more of the vegetal materials, this offers a rationale to explain the distinct properties of monozygotic twins derived from 2-cell embryos in mice.

developmental biology↗

bioRxiv2022

Intracellular fraction of zona pellucida protein 3 is required for the oocyte to embryo transition in mice

In oocyte biology the zona pellucida has long been known to operate three extracellular functions, namely, encasing the oocytes in ovarian follicles, mediating sperm-oocyte interaction and preventing premature embryo contact with maternal epithelia. The present study uncovers a fourth function that is fundamentally distinct from the other three, being critical for embryonic cell survival. Intriguingly, the three proteins of the mouse zona pellucida (ZP1, ZP2, ZP3) were found abundantly present also inside the embryo four days after fertilization, as shown by mass spectrometry, immunoblotting and immunofluorescence. Trim-away-mediated knockdown of ZPs in fertilized oocytes resulted in various grades of embryopathy: knockdown of ZP1 impeded blastocyst expansion, knockdown of ZP2 hampered the 2nd zygotic cleavage, while knockdown of ZP3 hampered the 1st zygotic cleavage - unlike the overexpression. Transcriptome analysis of ZP3-knockdown embryos pointed at defects of cytoplasmic translation in the context of embryonic genome activation. This conclusion was supported by reduced protein synthesis in the ZP3-knockdown and by the lack of cleavage arrest when knockdown was postponed from the 1-cell to the late 2-cell stage. These data place constraints on the long-standing notion that the zona pellucida proteins only operate in the extracellular space. We postulate that such noncanonical localization of ZP3 reflect novel roles in the embryos interior during the oocyte-to-embryo transition in mice. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/521410v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@18c0ca2org.highwire.dtl.DTLVardef@19168aeorg.highwire.dtl.DTLVardef@16f784forg.highwire.dtl.DTLVardef@143c4b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2022

Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism

Initiating drug use during adolescence increases the risk of developing addiction and psychiatric disorders later in life, with long-term outcomes varying according to sex and exact timing of use. Even though most individuals begin experimenting with drugs of abuse in adolescence, to date, the cellular and molecular underpinnings explaining differential sensitivity to detrimental drug effects remain unknown. The Netrin-1/DCC guidance cue system plays a critical role in the adolescent development of mesocorticolimbic dopamine circuitry, segregating the cortical and limbic pathways. Adolescent experiences, including exposure to drugs of abuse, can regulate Dcc expression in male mice, placing Netrin-1/DCC signaling as a potential molecular link between experience and enduring changes to circuitry and behavior. Here we show that exposure to a recreational-like regimen of amphetamine (AMPH) in adolescence induces sex- and age-specific alterations in Dcc expression in the ventral tegmental area. Female mice are protected against the deleterious long-term effects of AMPH-induced Dcc regulation by compensatory changes in the expression of its binding partner, Netrin-1. AMPH induces targeting errors in mesolimbic dopamine axons and triggers their ectopic growth to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to its enduring cognitive effects. Upregulating DCC receptor expression in dopamine neurons in adolescent males using a neuron-optimized CRISPR/dCas9 Activation System induces female-like protection against the persistent effects of AMPH in early adolescence on inhibitory control. Netrin-1/DCC signaling is therefore a molecular switch which can be differentially regulated in response to the same experience as function of age and sex of the individual, leading to divergent long-term outcomes associated with vulnerable or resilient phenotypes.

neuroscience↗

bioRxiv2020

Two Parallel Pathways Mediate Olfactory-Driven Backward Locomotion

Although animals switch to backward walking upon sensing an obstacle or danger in their path, the initiation and execution of backward locomotion is poorly understood. The discovery of Moonwalker Descending Neurons (MDNs), made Drosophila useful to study neural circuits underlying backward locomotion. MDNs were demonstrated to receive visual and mechanosensory inputs. However, whether other modalities converge onto MDNs and what are the neural circuits activating MDNs are unknown. We show that aversive but not appetitive olfactory input triggers MDN-mediated backward locomotion. We identify in each hemisphere, a single Moonwalker Subesophageal Zone neuron (MooSEZ), which triggers backward locomotion. MooSEZs act both upstream and in parallel to MDNs. Surprisingly, MooSEZs also respond mostly to aversive odor. Contrary to MDNs, blocking MooSEZs activity has little effect on odor-evoked backward locomotion. Thus, this work reveals another important modality input to MDNs in addition to a novel olfactory pathway and MDN-independent backward locomotion pathway.

neuroscience↗

bioRxiv2019

Early-life adversity is associated with differential gene expression in response to acute psychological stress: preliminary findings

ObjectiveExposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present study used a novel experimental design to test how young adults exposure to ELA influence neuroendocrine and inflammatory responses to acute stress.\n\nMaterials and methodsParticipants were 12 males (mean age= 21.25), half of whom endorsed at least three significant adverse events up to age 18 years ( ELA group), and half who confirmed zero ( controls). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of NR3C1, FKBP5 and NFKB1, and plasma levels of pro-inflammatory cytokines (IL-1{beta}, IL-6, IL-8 and TNF) over a 4-hour window post-test.\n\nResultsThe ELA group evinced significantly higher cortisol response and lower NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. Cortisol and group status interacted such that increase in cortisol predicted increase in both NR3C1 and NFKB1 expression among controls, but decrease in the ELA group. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups.\n\nConclusionOverall, we provide preliminary findings for the biological embedding of stress via a dynamic and dysregulated pattern evidenced in response to acute psychosocial stress. ELA may program physiological systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate these findings.

molecular biology↗

bioRxiv2019

Differential Treatment Benefit Prediction For Treatment Selection in Depression: A Deep Learning Analysis of STAR*D and CO-MED Data

BackgroundDepression affects one in nine people, but treatment response rates remain low. There is significant potential in the use of computational modelling techniques to predict individual patient responses and thus provide more personalized treatment. Deep learning is a promising computational technique that can be used for differential treatment selection based on predicted remission probability.\n\nMethodsUsing STAR*D and CO-MED trial data, we employed deep neural networks to predict remission after feature selection. Differential treatment benefit was estimated in terms of improvement of population remission rates after application of the model for treatment selection using both naive and conservative approaches. The naive approach assessed population remission rate in five sets of 200 patients held apart from the training set; the conservative approach used bootstrapping for sample generation and focused on population remission rate for patients who actually received the drug predicted by the model compared to the general population.\n\nResultsOur deep learning model predicted remission in a pooled CO-MED/STAR*D dataset (including four treatments) with an AUC of 0.69 using 17 input features. Our naive analysis showed an improvement of remission of over 30% (from a 34.33% population remission rate to 46.12%). Our conservative analysis showed a 7.2% improvement in population remission rate (p= 0.01, C.I. 2.48% {+/-} .5%).\n\nConclusionOur model serves as proof-of-concept that deep learning has utility in differential prediction of antidepressant response when selecting from a number of treatment options. These models may have significant real-world clinical implications.

neuroscience↗

bioRxiv2019

No Evidence for Associations Between the Big Five Personality Traits and Variability in Brain Gray or White Matter

Attempts to link the Big Five personality traits of Openness-to-Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism with variability in trait-like features of brain structure have produced inconsistent results. Small sample sizes and heterogeneous methodology have been suspected in driving these inconsistencies. Here, we tested for associations between the Big Five personality traits and multiple measures of brain structure using data from 1,107 university students (636 women, mean age 19.69{+/-}1.24 years) representing the largest attempt to date. In addition to replication analyses based on a prior study, we conducted exploratory whole-brain analyses. Four supplementary analyses were also conducted to examine 1) possible associations with lower-order facets of personality; 2) modulatory effects of sex; 3) effect of controlling for non-target personality traits; and 4) parcellation scheme effects. The analyses failed to identify any significant associations between the Big Five personality traits and variability in measures of cortical thickness, surface area, subcortical volume, or white matter microstructural integrity, except for an association between greater surface area of the superior temporal gyrus and lower scores on conscientiousness that explained 0.44% of the morphometric measures variance. Notably however, the latter association is largely not supported by previous studies. The supplementary analyses mirrored these largely null findings, suggesting they were not substantively biased by our choice of analytic model. Collectively, these results indicate that if there are direct associations between the Big Five personality traits and variability in brain structure, they are of likely very small effect sizes and will require very large samples for reliable detection.

neuroscience↗

bioRxiv2018

An integrated genome-wide multi-omics analysis of gene expression dynamics in the preimplantation mouse embryo

Early mouse embryos have an atypical translational machinery comprised of cytoplasmic lattices, poorly competent for translation. Thus, the impact of transcriptomic changes on the operational levels of proteins has likely been overestimated in the past. To find out, we used liquid chromatography-tandem mass spectrometry to detect and quantify 6,550 proteins in the oocyte and in six developmental stages (from zygote to blastocyst) collected in triplicates, and we also performed mRNA sequencing.\n\nIn contrast to the known split between the 2-cell and 4-cell stages at the transcript level, on the protein level the oocyte-to-embryo transition appeared to last until the morula stage. In general, protein abundance profiles were weakly correlated with those of their cognate mRNAs and we found little or no concordance between changes in protein and transcript expression relative to the oocyte at early stages. However, concordance increased towards morula and blastocyst, hinting at a more direct coupling of proteins with transcripts at these stages, in agreement with the increase in free ribosome abundance. Independent validation by immunofluorescence and qPCR confirmed the existence of genes featuring strongly positively and negatively correlated protein and transcript. Moreover, consistent coverage of most known protein complexes indicates that our dataset represents a large fraction of the expressed proteome. Finally, we identified 20 markers, including members of the endoplasmic reticulum pathway, for discriminating between early and late stages.\n\nThis resource contributes towards closing the gap between the predicted phenotype, based on mRNA, and the actual phenotype, based on protein, of the mouse embryo.

developmental biology↗

bioRxiv2018

PySight: plug and play photon counting for fast intravital microscopy

Imaging increasingly large neuronal populations at high rates pushed multi-photon microscopy into the photon-deprived regime. We present PySight, an add-on hardware and software solution tailored for photon-deprived imaging conditions. PySight more than triples the median amplitude of neuronal calcium transients in awake mice, and facilitates single-trial intravital voltage imaging in fruit flies. Its unique data streaming architecture allowed us to image a fruit flys olfactory response over 234 x; 600 x; 330{micro}m3 at 73 volumes per second, outperforming top-tier imaging setups while retaining over 200 times lower data rates. PySight requires no electronics expertise nor custom synchronization boards, and its open-source software is extensible to any imaging method based on single-pixel (bucket) detectors. PySight offers an optimal data acquisition scheme for ever increasing imaging volumes of turbid living tissue.

neuroscience↗