Biology subjects

Harel, N.

Publications and source records attributed to Harel, N..

At least 19 recordsLinked to original sources

bioRxiv2026

Temporal dynamics of RNA phage infection reveal bacterial recovery despite ongoing viral replication

Bacterial defenses against DNA phages are well documented, yet responses to RNA phages remain largely unexplored. Here, we characterize the population dynamics and host responses of Escherichia coli infected by the lytic RNA phage MS2 across multiple timescales, using bulk and single-cell transcriptomics, fluorescence microscopy, whole-genome sequencing, and genetic perturbations. Despite rapid viral takeover and extensive cell death, the bacterial population subsequently rebounds, revealing an unusual state in which host proliferation persists under intense phage pressure. Early in infection, heterogeneous subpopulations are evident, including one with low or undetectable viral transcript levels, low expression of the F-plasmid genes encoding the F-pilus (the MS2 receptor), and a distinct metabolic state. Strikingly, the rebounding population carries MS2 RNA in the great majority of cells, with evidence for active viral replication and continued cell division despite high viral loads. This rebound coincides with strong induction of biofilm-associated genes, including the pga operon, which synthesizes the biofilm-matrix exopolysaccharide PNAG. Deletion of pgaA causes earlier population decline and reduced population survival, indicating that pga-dependent matrix production delays viral lysis. Over longer timescales, phage-exposed populations show heterogeneous F-plasmid prevalence and plasmid-wide expression, consistent with dynamic cycling between plasmid-bearing and plasmid-free states: MS2 selects against F-plasmid-bearing cells, whereas conjugation may restore plasmid carriage. We propose that the biofilm-associated matrix delays viral lysis relative to continued cell division, long enough for rare F-plasmid-free daughter cells to arise and expand. Our results suggest that bacterial survival is determined by a dynamic race between viral lysis and host-cell division.

microbiology↗

bioRxiv2026

Prefrontal cortical pathways mediating cognitive control enhancement from internal capsule stimulation

BackgroundDeep brain stimulation (DBS) targeting the ventral internal capsule/ventral striatum (VCVS) is an effective treatment for several psychiatric disorders, but clinical responses often vary amongst patients likely due to an incomplete mechanistic understanding of the brain pathways mediating response. VCVS DBS can improve cognitive control, a core deficit in multiple psychiatric disorders. Here, we investigated which prefrontal cortical pathway(s) in the internal capsule are associated with improving cognitive control during VCVS DBS. MethodsFour participants with bilateral VCVS DBS completed the Multi-Source Interference Task (MSIT) under 27 stimulation settings varying by side (left/right lead), electrode, amplitude, and frequency. Each condition included 100 trials and response time (RT) assessed task performance. Personalized pathway activation models quantified axonal recruitment across 11 segmented prefrontal cortical fiber bundles per brain hemisphere. Associations between pathway activation and task RT were analyzed to identify circuits linked to improved cognitive control performance. ResultsRight-sided VCVS stimulation produced greater improvements in cognitive control (reductions in MSIT RT) than left-sided stimulation. Activation of right dorsal prefrontal cortical pathways connected to the dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC) most strongly predicted faster MSIT RTs, whereas no left-sided pathways were associated with performance changes. ConclusionsThese findings suggest that the effects of VCVS DBS on cognitive control are primarily mediated by right dorsal prefrontal cortical axons projecting from the dlPFC and dmPFC. Targeting these pathways may improve stimulation strategies and outcomes for psychiatric disorders characterized by impaired cognitive control.

neuroscience↗

bioRxiv2026

Functional MRI of the Human Hippocampus at 10.5T: Pushing the Boundaries of Spatial Resolution

Although the hippocampus is central to human cognition, its deep location within the medial temporal lobe has historically limited fMRI signal quality. Here, we leverage an ultrahigh-field 10.5T fMRI system, which provides inherently higher signal-to-noise ratio than commonly used lower-field systems, to overcome these limitations and achieve unprecedented 0.5 mm isotropic resolution. This advancement allows for comprehensive hippocampal coverage with robust image quality, facilitating the study of functional microcircuits in individual subjects and paving the way for high-precision clinical diagnostics.

neuroscience↗

bioRxiv2026

Entrenchment of germline amino-acid differences in antibody affinity maturation

Entrenchment -- epistasis that locks in amino acid differences between homologous proteins, so each disfavors substitutions toward the others state -- has been demonstrated along individual protein lineages over deep evolutionary time. Antibodies offer a unique system for studying entrenchment: multiple homologous germline V gene paralogs provide diverse starting points, and the rapid somatic evolution of affinity maturation generates dense phylogenies from which selection on germline-encoded residues can be inferred. Using DASM, a deep-learning model that separates selection from mutation in antibody repertoire data, we test for entrenchment across immunoglobulin heavy chain variable (IGHV) genes. We detect entrenchment at two levels of germline divergence, driven by different sources of epistasis. Within V gene families (up to [~]20% amino acid divergence), entrenched sites cluster at the borders of the complementarity-determining regions (CDRs, the antigen-binding loops) and show high germline diversity. These sites contact antigen, light chain, and the heavy chain CDR3 loop, all of which are encoded independently of the IGHV germline. This pattern is consistent with epistasis from genetically uncoupled partners. Between V gene families, at deeper levels of divergence (25-40%), entrenchment additionally includes positions in the framework scaffold distant from binding interfaces, suggesting a larger contribution from intra-heavy-chain structural constraints. Observed mutation frequencies in human repertoires corroborate these predictions where data are sufficient. Together, these results demonstrate that the rapid somatic evolution of antibodies can serve as a lens for revealing epistatic constraints acting on germline-encoded residues, including constraints imposed by genetically uncoupled partners assembled during B cell development.

evolutionary biology↗

bioRxiv2025

10.5 Tesla High-Resolution Macaque Brain MRI for Connectivity Studies

Mapping brain connectivity in primates remains a major challenge due to difficulties in resolving microscopic white matter architecture, while maintaining whole-brain coverage. Increasing imaging spatial resolution is key for disambiguating fibre configurations within smaller anatomical volumes. Here, we present novel developments that allow high-resolution diffusion MRI of the macaque brain using one of the world's highest-field human MRI scanners operating at 10.5 Tesla, allowing both in vivo and ex vivo macaque brain imaging. Our approach achieves very high spatial resolution across both tissue states, (up to 580 m)3 in vivo and (300 m)3 ex vivo, with diffusion weighting up to b = 6000 s/mm2. We detail methodological advances in data acquisition, image reconstruction, processing and whole-brain tractography that overcome critical challenges associated with ultra-high-field imaging. This work establishes a new framework for high-resolution in vivo and ex vivo neuroimaging of the NHP brain at 10.5 T using a human bore scanner, paving the way for subsequent analyses of brain connectivity across species and tissue states at unprecedented detail. The dataset, along with all processing pipelines, containerised workflows, and reusable web services, is openly shared to support reproducibility and future integration with microscopy for studying white matter microstructure and connections at the mesoscale.

neuroscience↗

bioRxiv2025

Diffusion-weighted steady-state free precession imaging in the ex vivo macaque brain on a 10.5T human MRI scanner

Diffusion MRI provides a non-invasive probe of local fibre bundles and long-range anatomical connections to characterise the structural connectome. One way to achieve very high spatial resolution diffusion MRI data for connectivity investigations is to scan ex-vivo brains over many hours or days, ideally at ultra-high field strength to boost signal levels. However, conventional diffusion MRI acquisition techniques do not generally deliver good data quality for the challenging conditions of ex-vivo tissue, characterised by reduced diffusivities and relaxation times when compared to in vivo. In this work, we investigate the potential of the diffusion-weighted steady-state free precession (DW-SSFP) sequence for ex vivo diffusion imaging of the macaque brain using a 10.5 T human MRI scanner with a conventional (Gmax = 70 mT/m) gradient set. SNR-efficiency optimisations incorporating experimental relaxation times demonstrate that the DW-SSFP sequence is predicted to achieve improved or similar SNR efficiency compared to a diffusion-weighted spin- and stimulated-echo sequence. Importantly, DW-SSFP can achieve this with the additional benefit of negligible geometric distortions, unlike conventional diffusion MRI using an echo-planar imaging readout. Using optimised DW-SSFP sequence parameters, we propose a protocol at 0.4 mm isotropic resolution using a two-shell multi-orientation protocol (effective b-values of 3200 s/mm2 and 5600 s/mm2). We fit the data using Tensor, Ball and 3-Sticks and Constrained Spherical Deconvolution signal representations. The results demonstrate high-quality diffusivity estimates across the entire brain with the ability to resolve multiple fibre populations in challenging crossing-fibre regions. The data will be made fully open source and multimodal as part of the Center for Mesoscale Connectomics, providing a resource for future connectivity investigations.

neuroscience↗

bioRxiv2024

Navigating a fine balance: point-mutant cheater viruses disrupt the viral replication cycle

Cheater viruses, alternatively denoted as defective interfering viruses, cannot replicate on their own yet replicate faster than the wild type (WT) when the two viruses coinfect the same cell. Cheaters must possess dual genetic features: a defect, which leads to their inability to infect cells on their own, and a selective advantage over WT during co-infection. Previously, we have discovered two point-mutant cheaters of the MS2 bacteriophage. Here, we set out to discover the possible repertoire of cheater MS2 viruses by performing experimental evolution at a very high multiplicity of infection (MOI). Our results revealed a third point-mutant cheater that arose in eight biological replicas. Each of the three cheaters disrupts the fine balance necessary for phage replication, in different ways that create a defect + advantage. We found that over time, the point mutant cheaters accumulate additional "helper" mutations, which alter other stages of the viral replication cycle, complementing the disruptions created by the original cheater. Intriguingly, cheater and helper mutations almost always reside in very close proximity on the genome. This region encodes for multiple functions: overlapping reading frames as well as overlapping RNA structures critical for transitioning from one stage to another in the viral replication cycle. This region of overlap explains the dual functions of cheaters, as one mutation can have pleiotropic effects. Overall, these findings underscore how viruses, whose dense genomes often have overlapping functions, can easily evolve point-mutant cheaters, and how cheaters can evolve to alter the intricate balance of the viral replication cycle.

evolutionary biology↗

bioRxiv2024

Mapping polarization-sensitive optical coherence tomography and ultra-high-field diffusion MRI in the macaque brain

This paper provides comparisons between microstructure and two-dimensional fiber orientations measured optically using polarization sensitive optical coherence tomography (PS-OCT) and those estimated from ultra-high-field diffusion MRI (dMRI) at 10.5T in the macaque brain. The PS-OCT imaging is done at an in-plane resolution of [~]10 microns in and around the thalamus. Whole brain dMRI is acquired at an isotropic resolution of 0.75 mm. We provide comparisons between cross-polarization and optical orientation from PS-OCT with the fractional anisotropy and two-dimensional orientations extracted from dMRI using a diffusion tensor model. The orientations from PS-OCT are also extracted computationally using a structure tensor. Additionally, we demonstrate the utility of mesoscale, PS-OCT imaging in improving the MRI resolution by learning the mapping between these contrasts using a super-resolution Generative Adversarial Network.

neuroscience↗

bioRxiv2022

REM Sleep Movements in Parkinson's Disease: Is the Basal Ganglia Engaged?

To elucidate the role of the basal ganglia during REM sleep movements in Parkinsons disease (PD) we recorded pallidal neural activity from four PD patients. Unlike desynchronization commonly observed during wakeful movements, beta oscillations (13-35 Hz) synchronized during REM sleep movements; furthermore, high-frequency oscillations (150-350 Hz) synchronized during movement irrespective of sleep-wake states. Our results demonstrate differential engagement of the basal ganglia during REM sleep and awake movements.

neuroscience↗

bioRxiv2021

Parkinsonian gait effects with DBS are associated with pallido-peduncular axis activation

BackgroundDeep brain stimulation (DBS) targeting the subthalamic nucleus (STN) often shows variable outcomes on treating gait dysfunction in Parkinsons disease (PD). Such variability may stem from which specific neuronal pathways are modulated by DBS and the extent to which those pathways are modulated relative to one another. ObjectiveLeveraging ultra-high-field (7T) imaging data and subject-specific computational models, this study investigated how activation of seven distinct pathways in and around STN, including the pallidopeduncular and pedunculopallidal pathways, affect step length at clinically-optimized STN-DBS settings. MethodsPersonalized computational models were developed for 10 subjects with a clinical diagnosis of PD and with bilateral STN-DBS implants. ResultsThe subject-specific pathway activation models showed a significant positive association between activation of the pedunculopallidal pathway and increased step length, and negative association on step length with pallidopeduncular pathway and hyperdirect pathway activation. ConclusionsThe STN region includes multiple pathways, including fibers of passage to and from the mesencephalic locomotor area. Future clinical optimization of STN-DBS should consider these fibers of passage in the context of treating parkinsonian gait.

neuroscience↗

bioRxiv2021

Controlling pallidal oscillations in real-time in Parkinson's disease using evoked interference deep brain stimulation (eiDBS): proof of concept in the human

Approaches to control basal ganglia neural activity in real-time are needed to clarify the causal role of 8-35 Hz ("beta band") oscillatory dynamics in the manifestation of Parkinsons disease (PD) motor signs. Here, we show that resonant beta oscillations evoked by electrical pulse with precise amplitude and timing can be used to predictably suppress or amplify spontaneous beta band activity in the internal segment of the globus pallidus (GPi) in the human. Using this approach, referred to as closed-loop evoked interference deep brain stimulation (eiDBS), we could suppress or amplify frequencyspecific (16-22 Hz) neural activity in a PD patient. Our results highlight the utility of eiDBS to characterize the role of oscillatory dynamics in PD and other brain conditions, and to develop personalized neuromodulation systems.

neuroscience↗

bioRxiv2020

Deep-learning based fully automatic segmentation of the globus pallidus interna and externa using ultra-high 7 Tesla MRI

Deep brain stimulation (DBS) surgery has been shown to dramatically improve the quality of life for patients with various motor dysfunctions, such as those afflicted with Parkinsons disease (PD), dystonia, and essential tremor (ET), by relieving motor symptoms associated with such pathologies. The success of DBS procedures is directly related to the proper placement of the electrodes, which requires the ability to accurately detect and identify relevant target structures within the subcortical basal ganglia region. In particular, accurate and reliable segmentation of the globus pallidus (GP) interna is of great interest for DBS surgery for PD and dystonia. In this work, we present a deep-learning based neural network, which we term GP-net, for the automatic segmentation of both the external and internal segments of the globus pallidus. High resolution 7 Tesla images from 101 subjects were used in this study; GP-net is trained on a cohort of 58 subjects, containing patients with movement disorders as well as healthy control subjects. GP-net performs 3D inference in a patient-specific manner, alleviating the need for atlas-based segmentation. GP-net was extensively validated, both quantitatively and qualitatively over 43 test subjects including patients with movement disorders and healthy control and is shown to consistently produce improved segmentation results compared with state-of-the-art atlas-based segmentations. We also demonstrate a post-operative lead location assessment with respect to a segmented globus pallidus obtained by GP-net.

neuroscience↗

bioRxiv2020

An 8 Dipole Transceive and 24 Loop Receive Array for Non-Human Primate Head Imaging at 10.5T

A 32-channel RF coil was developed for brain imaging of anesthetized non-human primates (Rhesus Macaque) at 10.5 tesla. The coil is composed of an 8-channel dipole transmit/receive array, close-fitting 16-channel loop receive array headcap, and 8-channel loop receive array lower insert. The transceiver dipole array is composed of eight end-loaded dipole elements self-resonant at the 10.5 tesla proton Larmor frequency. These dipole elements were arranged on a plastic cylindrical former which was split in two to allow for convenient animal positioning. Nested into the bottom of the dipole array former is located an 8-channel loop receive array which contains 5x10 cm2 square loops arranged in two rows of four loops. Arranged in a close-fitting plastic headcap is located a high-density 16-channel loop receive array. This array is composed of 14 round loops 37 mm in diameter and two partially detachable, irregularly shaped loops that encircle the ears. Imaging experiments were performed on anesthetized non-human primates on a 10.5 tesla MRI system equipped with body gradients with a 60 cm open bore. The coil enabled submillimeter (0.58 mm isotropic) high resolution anatomical and functional imaging as well as tractography of fasciculated axonal bundles. The combination of a close-fitting loop receive array and dipole transceiver array allowed for a higher channel count receiver and consequent higher SNR and parallel imaging gains. Parallel imaging performance supports high resolution fMRI and dMRI with a factor of three reduction in sampling. The transceive array elements during reception contributed approximately one quarter of SNR in the lower half of the brain which was farthest from the close-fitting headcap receive array.

bioengineering↗

bioRxiv2020

High-frequency oscillations in the internal globus pallidus: a pathophysiological biomarker in Parkinson's disease?

Abnormal oscillatory neural activity in the basal ganglia is thought to play a pathophysiological role in Parkinsons disease. Many patient studies have focused on beta frequency band (13-35 Hz) local field potential activity in the subthalamic nucleus, however increasing evidence points to alterations in neural oscillations in high frequency ranges (>100 Hz) having pathophysiological relevance. Prior studies have found that power in subthalamic high frequency oscillations (HFOs) is positively correlated with dopamine tone and increased during voluntary movements, implicating these brain rhythms in normal basal ganglia function. Contrary to this idea, in the current study we present a combination of clinical and preclinical data that support the hypothesis that HFOs in the internal globus pallidus (GPi) are a pathophysiological feature of Parkinsons disease. Spontaneous and movement-related pallidal field potentials were recorded from deep brain stimulation (DBS) leads targeting the GPi in five externalized Parkinsons disease patients, on and off dopaminergic medication. We identified a prominent oscillatory peak centered at 200-300 Hz in the off-medication rest recordings in all patients. High frequency power increased during movement, and the magnitude of modulation was negatively correlated with bradykinesia. Moreover, high frequency oscillations were significantly attenuated in the on-medication condition, suggesting they are a feature of the parkinsonian condition. To further confirm that GPi high frequency oscillations are characteristic of dopamine depletion, we also collected field potentials from DBS leads chronically implanted in three rhesus monkeys before and after the induction of parkinsonism with the neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). High frequency oscillations and their modulation during movement were not prominent in the normal condition but emerged in the parkinsonian condition in the monkey model. These data provide the first evidence demonstrating that exaggerated, movement-modulated high frequency oscillations in the internal globus pallidus are a pathophysiological feature of Parkinsons disease, and motivate additional investigations into the functional roles of high frequency neural oscillations across the basal ganglia-thalamocortical motor circuit and their relationship to motor control in normal and diseased states. These findings also provide rationale for further exploration of these signals for electrophysiological biomarker-based device programming and stimulation strategies in patients receiving deep brain stimulation therapy.

neuroscience↗

bioRxiv2020

Ultra-high field (10.5 T) resting state fMRI in the macaque

Resting state functional connectivity refers to the temporal correlations between spontaneous hemodynamic signals obtained using functional magnetic resonance imaging. This technique has demonstrated that the structure and dynamics of identifiable networks are altered in psychiatric and neurological disease states. Thus, resting state network organizations can be used as a diagnostic, or prognostic recovery indicator. However, much about the physiological basis of this technique is unknown. Thus, providing a translational bridge to an optimal animal model, the macaque, in which invasive circuit manipulations are possible, is of utmost importance. Current approaches to resting state measurements in macaques face unique challenges associated with signal-to-noise, the need for invasive contrast agents, and within-subject designs. These limitations can, in principle, be overcome through ultra-high magnetic fields. However, ultra-high field imaging has yet to be adapted for fMRI in macaques. Here, we demonstrate that the combination of high channel count transmitter and receiver arrays, optimized pulse sequences, and careful anesthesia regimens, allows for detailed within-subject resting state analysis at ultra-high resolutions. In this study, we uncover thirty spatially detailed resting state components that are highly robust across individual macaques and closely resemble the quality and findings of connectomes from large human datasets. This detailed map of the rsfMRI macaque connectome will be the basis for future neurobiological circuit manipulation work, providing valuable biological insights into human connectomics.

neuroscience↗

bioRxiv2020

Suppressing and amplifying neural oscillations in real-time using phase-locked electrical stimulation: concept, optimization and in-vivo testing

BackgroundApproaches to predictably control neural oscillations are needed to understand their causal role in brain function in healthy or diseased states and to advance the development of neuromodulation therapies. In this study, we present a closed-loop neural control and optimization framework to actively suppress or amplify low-frequency neural oscillations observed in local field potentials in real-time by using electrical stimulation. Objective/HypothesisThe rationale behind this control approach and our working hypothesis is that neural oscillatory activity evoked by electrical pulses can suppress or amplify spontaneous oscillations via destructive or constructive interference when stimulation pulses are continuously delivered with appropriate amplitudes and at precise phases of these oscillations in a closed-loop scheme. MethodsWe tested our hypothesis in two nonhuman primates that exhibited a robust increase in low-frequency (8-30 Hz) oscillatory power in the subthalamic nucleus (STN) following administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To test our neural control approach, we targeted 8-17 Hz oscillations and used electrode arrays and electrical stimulation waveforms similar to those used in humans chronically implanted with brain stimulation systems. Stimulation parameters that maximize the suppression or amplification of neural oscillations were predicted using mathematical models of the stimulation evoked oscillations. ResultsOur neural control and optimization approach was capable of actively and robustly suppressing or amplifying oscillations in the targeted frequency band (8-17 Hz) in real-time in the studied subjects. ConclusionsThe results from this study support our hypothesis and suggest that the proposed neural control framework allows one to characterize in controlled experiments the functional role of frequency-specific neural oscillations by using electrodes and stimulation waveforms currently being employed in humans.

neuroscience↗

bioRxiv2019

Sequencing Complete Genomes of RNA Viruses With MinION Nanopore: Finding Associations Between Mutations

One of the key challenges in the field of genetics is the inference of haplotypes from next generation sequencing data. The MinION Oxford Nanopore sequencer allows sequencing long reads, with the potential of sequencing complete genes, and even complete genomes of viruses, in individual reads. However, MinION suffers from high error rates, rendering the detection of true variants difficult. Here we propose a new statistical approach named AssociVar, which differentiates between true mutations and sequencing errors from direct RNA/DNA sequencing using MinION. Our strategy relies on the assumption that sequencing errors will be dispersed randomly along sequencing reads, and hence will not be associated with each other, whereas real mutations will display a non-random pattern of association with other mutations. We demonstrate our approach using direct RNA sequencing data from evolved populations of the MS2 bacteriophage, whose small genome makes it ideal for MinION sequencing. AssociVar inferred several mutations in the phage genome, which were corroborated using parallel Illumina sequencing. This allowed us to reconstruct full genome viral haplotypes constituting different strains that were present in the sample. Our approach is applicable to long read sequencing data from any organism for accurate detection of bona fide mutations and inter-strain polymorphisms.

genetics↗

bioRxiv2018

Automatic Localization of the Subthalamic Nucleus on Patient-Specific Clinical MRI by Incorporating 7T MRI and Machine Learning: Application in Deep Brain Stimulation

Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) has shown clinical potential for relieving the motor symptoms of advanced Parkinsons disease. While accurate localization of the STN is critical for consistent across-patients effective DBS, clear visualization of the STN under standard clinical MR protocols is still challenging. Therefore, intraoperative microelectrode recordings (MER) are incorporated to accurately localize the STN. However, MER require significant neurosurgical expertise and lengthen the surgery time. Recent advances in 7T MR technology facilitate the ability to clearly visualize the STN. The vast majority of centers, however, still do not have 7T MRI systems, and fewer have the ability to collect and analyze the data. This work introduces an automatic STN localization framework based on standard clinical MRIs without additional cost in the current DBS planning protocol. Our approach benefits from a large database of 7T MRI and its clinical MRI pairs. We first model in the 7T database, using efficient machine learning algorithms, the spatial and geometric dependency between the STN and its adjacent structures (predictors). Given a standard clinical MRI, our method automatically computes the predictors and uses the learned information to predict the patient-specific STN. We validate our proposed method on clinical T2W MRI of 80 subjects, comparing with experts-segmented STNs from the corresponding 7T MRI pairs. The experimental results show that our framework provides more accurate and robust patient-specific STN localization than using state-of-the-art atlases. We also demonstrate the clinical feasibility of the proposed technique assessing the post-operative electrode active contact locations.

neuroscience↗