Biology subjects

Ray, S.

Publications and source records attributed to Ray, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Blunted anterior midcingulate response to reward in opioid users is normalized by prefrontal transcranial magnetic stimulation

IntroductionAbnormalities in goal-directed behavior, mediated by mesocorticolimbic reward function and structure, contribute to worse clinical outcomes including higher risk of treatment dropout and drug relapse in opioid users (OU). Material and MethodIn a sham-controlled randomized study design, we measured whether robot-assisted 10Hz transcranial magnetic stimulation (TMS) applied to the prefrontal cortex was able to modulate anterior midcingulate cortex (MCC) electrophysiological response to rewards, in OU and matched healthy controls. ResultsWe show that OU exhibit a blunted anterior MCC reward response, compared to healthy controls (t(39) = 2.62, p = 0.01, d = 0.84), and that this is normalized following 10-Hz excitatory TMS (t(36) = .82, p = 0.42, d = 0.17). ConclusionsExcitatory TMS modulated the putative reward function of the MCC in OU. Further work with increased sample sizes and TMS sessions is required to determine whether restoring MCC reward function increases reward-directed behaviors, which may enhance treatment success through the maintenance of treatment goals.

neuroscience↗

bioRxiv2024

Burst Estimation through Atomic Decomposition (BEAD): A Toolbox to find Oscillatory Bursts in Brain Signals

Recent studies have shown that brain signals often show oscillatory bursts of short durations, which have been linked to various aspects of computation and behavior. Traditional methods often use direct spectral estimators to estimate the power of brain signals in spectral and temporal domains, from which bursts are identified. However, direct spectral estimators are known to be noisy, such that even stable oscillations may appear bursty. We have previously shown that the Matching Pursuit (MP) algorithm, which uses a large overcomplete dictionary of basis functions (called "atoms") to decompose the signal directly in the time domain, partly addresses this concern and robustly finds long bursts in synthetic as well as real data. However, MP is a greedy algorithm that can give non-optimal solutions and requires a large-sized dictionary. To address these concerns, we extended two other algorithms - orthogonal MP (OMP) and OMP using Multiscale Adaptive Gabor Expansion (OMP-MAGE), to perform burst duration estimation. We also develop a novel algorithm, called OMP using Gabor Expansion with Atom Reassignment (OMP-GEAR). These algorithms overcome the limitations of MP and can work with a significantly smaller dictionary size. We find that, in synthetic data, OMP, OMP-MAGE and OMP-GEAR converge faster than MP. Also, OMP-MAGE and OMP-GEAR outperform both MP and OMP when the dictionary size is small. Finally, OMP-GEAR significantly outperforms OMP-MAGE when the bursts are overlapping. Importantly, the burst durations obtained using MP and OMP with a very large-sized dictionary are comparable to that obtained using OMP-MAGE with a much smaller-sized dictionary in real data obtained from two monkeys passively viewing static gratings which induced gamma bursts in the primary visual cortex. OMP-GEAR yields slightly smaller burst durations, but all the estimated burst durations are still significantly larger than the duration estimated using traditional methods. These results suggest that gamma bursts are longer than previously reported. Raw data from two monkeys, as well as codes for both traditional and new methods, are publicly available as part of this toolbox.

neuroscience↗

bioRxiv2024

A Single Trophoblast Layer Acts as the Gatekeeper at the Endothelial-Hematopoietic Crossroad in the Placenta

During embryonic development the placental vasculature acts as a major hematopoietic niche, where endothelial to hematopoietic transition ensures emergence of hematopoietic stem cells (HSCs). However, the molecular mechanisms that regulate the placental hematoendothelial niche are poorly understood. Using a parietal trophoblast giant cell (TGC)-specific knockout mouse model and single-cell RNA-sequencing, we show that the paracrine factors secreted by the TGCs are critical in the development of this niche. Disruptions in the TGC-specific paracrine signaling leads to the loss of HSC population and the concomitant expansion of a KDR+/DLL4+/PROM1+ hematoendothelial cell-population in the placenta. Combining single- cell transcriptomics and receptor-ligand pair analyses, we also define the parietal TGC- dependent paracrine signaling network and identify Integrin signaling as a fundamental regulator of this process. Our study elucidates novel mechanisms by which non-autonomous signaling from the primary parietal TGCs maintain the delicate placental hematopoietic- angiogenic balance and ensures embryonic and extraembryonic development.

developmental biology↗

bioRxiv2024

METTL3 shapes m6A epitranscriptomic landscape for successful human placentation

Methyltransferase-like 3 (METTL3), the catalytic enzyme of methyltransferase complex for m6A methylation of RNA, is essential for mammalian development. However, the importance of METTL3 in human placentation remains largely unexplored. Here, we show that a fine balance of METTL3 function in trophoblast cells is essential for successful human placentation. Both loss-of and gain-in METTL3 functions are associated with adverse human pregnancies. A subset of recurrent pregnancy losses and preterm pregnancies are often associated with loss of METTL3 expression in trophoblast progenitors. In contrast, METTL3 is induced in pregnancies associated with fetal growth restriction (FGR). Our loss of function analyses showed that METTL3 is essential for the maintenance of human TSC self-renewal and their differentiation to extravillous trophoblast cells (EVTs). In contrast, loss of METTL3 in human TSCs promotes syncytiotrophoblast (STB) development. Global analyses of RNA m6A modification and METTL3-RNA interaction in human TSCs showed that METTL3 regulates m6A modifications on the mRNA molecules of critical trophoblast regulators, including GATA2, GATA3, TEAD1, TEAD4, WWTR1, YAP1, TFAP2C and ASCL2, and loss of METTL3 leads to depletion of mRNA molecules of these critical regulators. Importantly, conditional deletion of Mettl3 in trophoblast progenitors of an early post-implantation mouse embryo also leads to arrested self-renewal. Hence, our findings indicate that METLL3 is a conserved epitranscriptomic governor in trophoblast progenitors and ensures successful placentation by regulating their self-renewal and dictating their differentiation fate.

developmental biology↗

bioRxiv2024

Delayed accumulation of inhibitory input explains gamma frequency variation with changing contrast in an Inhibition Stabilized Network

Gamma rhythm (30-70 Hz), thought to represent the push-pull activity of excitatory and inhibitory population, can be induced by presenting achromatic gratings in the primary visual cortex (V1) and is sensitive to stimulus properties such as size and contrast. In addition, gamma occurs in short bursts, and shows a "frequency-falloff" effect where its peak frequency is high after stimulus onset and slowly decreases to a steady state. Recently, these size-contrast properties and temporal characteristics were replicated in a self-oscillating Wilson-Cowan (WC) model operating as an Inhibition stabilized network (ISN), stimulated by Ornstein-Uhlenbeck (OU)-type inputs. In particular, frequency-falloff was explained by delayed and slowly accumulated inputs arriving at local inhibitory populations. We hypothesized that if the stimulus is preceded by another higher contrast stimulus, frequency-falloff could be abolished or reversed, since the excessive inhibition will now take more time to dissipate. We presented gratings at different contrasts consecutively to two female monkeys while recording gamma using microelectrode arrays in V1 and confirmed this prediction. Further, this model also replicated a characteristic pattern of gamma frequency modulation to counter-phasing stimuli as reported previously. Thus, the ISN model with delayed surround input replicates gamma frequency responses to time-varying contrasts. Significance statementGamma rhythms represent sustained push-pull dynamics between excitatory and inhibitory populations during visual stimulation. Gamma power and centre frequency varies depending on stimulus features, and onset of stimulus produces a "frequency-fall" trend where onset frequency is higher and subsequently plateaus to a lower value. In an earlier work, we argued, using a noisy rate-model of V1, that a delayed onset of inhibition-drive from the surround populations produced the gamma frequency-falloff. We tested a key prediction of this hypothesis that the frequency-falloff can be abolished or reversed if the stimulus is preceded by a higher contrast stimulus, and confirmed the same by recording from primate primary visual cortex while presenting multiple stimuli consecutively at varying contrasts.

neuroscience↗

bioRxiv2024

Age-related changes in Higuchi's fractal dimension in healthy human EEG are anti-correlated with changes in oscillatory power and 1/f slope

Non-linear dynamical methods such as Higuchis fractal dimension (HFD) are often used to study the complexities of brain activity. In human electroencephalogram (EEG), while power in the gamma band (30-70 Hz) and the slope of the power spectral density (PSD) have been shown to reduce with healthy aging, there are conflicting findings regarding how HFD and other measures of complexity vary with aging. Further, the dependence of HFD on features obtained from PSD (such as gamma power and slope) has not been thoroughly probed. To address these issues, we computed time and frequency resolved HFD for EEG data collected from elderly population (N=217), aged between 50-88 years, for baseline (BL) eyes open state and during a fixation task in which visual grating stimuli that induce strong gamma oscillations were presented. During BL, HFD increased with age for frequencies up to 150 Hz, but surprisingly showed an opposite trend at higher frequencies. Interestingly, this change in HFD was opposite to the age-related change in PSD 1/f slope. Further, stimulus-related changes in HFD were anti-correlated with the changes in oscillatory power. However, age classification using HFD was slightly better than classification using spectral features (power and slope). Further, stimulus and age-related changes in HFD persisted even after normalization with surrogates, showing the effect of non-linear dynamics on HFD. Therefore, HFD could be jointly sensitive to various spectral features as well as some non-linearities not captured using spectral analysis, which could enhance our understanding of brain dynamics underlying healthy aging.

neuroscience↗

bioRxiv2024

Integration of Biological Data via NMF for Identification of Human Disease-Associated Gene Modules through Multi-label Classification.

Extensive evidence recognizes that proteins associated with several diseases frequently interact with each other. This leads to develop different network-based methods for uncovering the molecular workings of human diseases. These methods are based on the idea that protein interaction networks act as maps, where diseases manifest as localized perturbations within a neighborhood. Identifying these areas, known as disease modules, is essential for in-depth research into specific disease characteristics. While many computational methods have been developed the underlying connectivity patterns within these modules still yet to be explored. This work aim to fill this gap by integrating multiple biological data sources through non-negative matrix factorization (NMF) technique. We leverage two biological sources of information, protein-protein interactions (PPIs) and Gene Ontology data to find connections between novel genes and diseases. The data sources are first converted into networks, which are then clustered to obtain modules. Two types of modules are then integrated through NMF-based technique to obtain a set of meta-modules which preserve the essential characteristics of interaction patterns and functional similarity information among the proteins/genes. We assign multiple labels to each meta-module based on the statistical and biological properties they shared with the disease dataset. A multi-label classification technique is utilized to assign new disease labels to genes within each meta-modules. A total of 3131 gene-disease associations are identified, which are also validated through a literature survey, gene ontology and pathway-based analysis.

bioinformatics↗

bioRxiv2024

Comparing physiological impacts of positive pressure ventilation versus self-breathing via a versatile cardiopulmonary model incorporating a novel alveoli opening mechanism

Mathematical models can be used to generate high-fidelity simulations of the cardiopulmonary system. Such models, when applied to real patients, can provide valuable insights into underlying physiological processes that are hard for clinicians to observe directly. In this work, we propose a novel modelling strategy capable of generating scenario-specific cardiopulmonary simulations to replicate the vital physiological signals clinicians use to determine the state of a patient. This model is composed of a tree-like pulmonary system that features a novel, non-linear alveoli opening strategy, based on the dynamics of balloon inflation, that interacts with the cardiovascular system via the thorax. A baseline simulation of the model is performed to measure the response of the system during spontaneous breathing which is subsequently compared to the same system under mechanical ventilation. To test the new lung opening mechanics and systematic recruitment of alveolar units, a positive end-expiratory pressure (PEEP) test is performed and its results are then compared to simulations of a deep spontaneous breath. The system displays a marked decrease in tidal volume as PEEP increases, replicating a sigmoidal curve relationship between volume and pressure. At high PEEP, cardiovascular function is shown to be visibly impaired, in contrast to the deep breath test where normal function is maintained.

physiology↗

bioRxiv2024

Amyloid Beta Oligomers Accelerate ATP-Dependent Phase Separation of Ago2 to RNA Processing Bodies

Phase separation to insoluble membrane-less organelles is a major way of activity regulation of specific proteins in eukaryotic cells. miRNA-repressed mRNAs and Ago proteins are known to be localized to RNA-processing bodies, the subcellular structures which are formed due to assembly of several RNA binding and regulatory proteins in eukaryotic cells. Ago2 is the most important miRNA binding protein that by forming complex with miRNA binds to mRNAs having cognate miRNA binding sites and represses protein synthesis in mammalian cells. Factors which control compartmentalization of Ago2 and miRNA-repressed mRNAs to RNA processing bodies are largely unknown. We have adopted a detergent permeabilized cell-based assay system to follow the phase separation of exogenously added Ago2 to RNA processing bodies in vitro. The Ago2 phase separation process is ATP dependent and is influenced by osmolarity and salt concentration of the reaction buffer. miRNA binding of Ago2 is essential for its targeting to RNA processing bodies and the compartmentalization process gets retarded by miRNA binding "sponge" protein HuR. This assay system found to be useful in identification of amyloid beta oligomers as miRNA-activity modulators which repress miRNA activity by enhancing Ago2-miRNP targeting to RNA processing bodies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/584939v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1fe06eeorg.highwire.dtl.DTLVardef@7904b1org.highwire.dtl.DTLVardef@1231746org.highwire.dtl.DTLVardef@cd1405_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LImiRNA bound Ago2 gets phase separated in vitro to RNA processing bodies (PBs) in detergent permeabilized mammalian cells. C_LIO_LIPhase separation of Ago2 to PBs is controlled by presence of ATP and RNA. C_LIO_LIAmyloid beta oligomers retard dynamics of Ago2 bodies to inhibit miRNA function and enhance PB targeting of Ago2 miRNPs. C_LIO_LImicroRNA binding protein HuR can rescue Ago2 miRNP from PBs and inverse the effect of amyloid beta oligomers. C_LI

neuroscience↗

bioRxiv2024

Enhanced stimulus-induced and stimulus-free gamma in open-eye meditators

Visual stimuli induce "narrowband" gamma oscillations (30-70 Hz) that are linked to attention/binding and attenuate with aging and neurodegeneration. In contrast, meditation increases power in a broad frequency range (>25 Hz). However, the effect of meditation on stimulus-induced gamma is unknown. We recorded EEG from meditators and controls performing open-eye meditation while gamma-inducing stimuli were presented before, during and after meditation. We found that stimulus-induced gamma, like stimulus-free gamma, was stronger in meditators. Interestingly, both gamma signatures co-existed during meditation but were unrelated and prominent in occipital and fronto-temporal regions, respectively. Further, power spectral density (PSD) slope, which becomes shallower with aging, was steeper for meditators. Meditation could boost inhibitory mechanisms leading to stronger gamma and steeper PSDs, potentially providing protection against aging and neurodegeneration. One line summaryStimulus-induced and stimulus-free gamma are stronger in open-eye meditators.

neuroscience↗

bioRxiv2024

Stimulus-induced gamma sources weaken but not shrink with healthy aging in human EEG

Aging alters brain structure and function, and studying such changes may help understand the neural basis underlying aging and devise interventions to detect deviations from healthy progression. Electroencephalogram (EEG) offers an effective way to study healthy aging owing to its high temporal resolution and affordability. Recent studies have shown that narrow- band stimulus-induced gamma oscillations (20-70 Hz) in EEG, induced with cartesian gratings in a fixation task paradigm, weaken with healthy aging and onset of Alzheimers Disease (AD) while remaining highly reproducible for a given subject, and thus hold promise as potential biomarkers. However, functional connectivity (FC) sometimes changes in a different way compared to sensor power with aging. This difference could be potentially addressed by studying how underlying gamma sources change with aging, since either a reduction in source power or a shrinkage of the sources (or both) could reduce the power in the sensors but may have different effects on other measures such as FC. We therefore reconstructed EEG gamma sources through a linear inverse method called exact Low-resolution Tomography Analysis (eLORETA) on a large (N=217) cohort of healthy elderly subjects (>50 years). We further characterized gamma distribution in cortical space as an exponential fall-off from a seed voxel with maximal gamma source power to delineate a reduction in magnitude versus shrinkage. We found significant reduction in magnitude but not shrinkage with healthy aging. Overall, our results shed light on changes in EEG gamma source distribution with healthy aging, which could provide clues about underlying neural mechanisms.

neuroscience↗

bioRxiv2024

Auditory and visual gratings elicit distinct gamma responses

Sensory stimulation is often accompanied by fluctuations at high frequencies (>30Hz) in brain signals. These could be "narrowband" oscillations in the gamma band (30-70 Hz) or non-oscillatory "broadband" high-gamma (70-150 Hz) activity. Narrowband gamma oscillations, which are induced by presenting some visual stimuli such as gratings and have been shown to weaken with healthy aging and the onset of Alzheimers Disease, hold promise as potential biomarkers. However, since delivering visual stimuli is cumbersome as it requires head stabilization for eye tracking, an equivalent auditory paradigm could be useful. Although simple auditory stimuli have been shown to produce high-gamma activity, whether specific auditory stimuli can also produce narrowband gamma oscillations is unknown. We tested whether auditory ripple stimuli, which are considered an analogue to visual gratings, could elicit narrowband oscillations in auditory areas. We recorded 64-channel EEG from male and female (18 each) subjects while they either passively fixated on the monitor while viewing static visual gratings, or listened to stationary and moving ripples, played using loudspeakers, with their eyes open or closed. We found that while visual gratings induced narrowband gamma oscillations with suppression in the alpha band (8-12Hz), auditory ripples did not produce narrowband gamma but instead elicited very strong broadband high-gamma response and suppression in the beta band (14-26Hz). Even though we used equivalent stimuli in both modalities, our findings indicate that the underlying neuronal circuitry may not share ubiquitous strategies for stimulus processing. Significance statementIn the visual cortex, gratings can induce robust narrowband gamma oscillations (30-70Hz). These visual stimulus-induced oscillations can further be used as a biomarker for diagnosing neuronal disorders. However, tasks used to elicit these oscillations are challenging for elderly subjects, and therefore, we tested if we could use auditory stimuli instead. We hypothesized that auditory ripple stimuli, which are analogous to visual gratings, may elicit these narrowband oscillations. We found that ripples induce a broadband high-gamma response (70-150Hz) in human EEG, unlike visual gratings that produce robust gamma. Thus, the underlying neural circuitry in the two areas may not be canonical.

neuroscience↗

bioRxiv2024

3-epicaryoptin induces G2/M phase cell cycle arrest and apoptosis in human breast cancer cells by disrupting the microtubule network, an in vitro and in silico investigation

Breast cancer (BC) is a prevalent form of cancer observed in women across the globe, constituting over a quarter of all female BC cases. The treatment of BC continues to require significant efficacy, aiming to achieve high success rates while minimizing adverse effects on the body as a whole. In the current study, 3-epicaryoptin was tested for the molecular mechanism of its anti-cancer activity in the human breast cancer cell line, MCF-7. We investigated cell viability by MTT assay, cell cycle kinetics and apoptosis, immunofluorescence straining, molecular modelling, and ADMET profiling. MTT assay results showed that 3-epicaryoptin was found cytotoxic against MCF-7 cells with an IC50 value of 344.64 {micro}g mL-1 for 48 h. Flow cytometric analysis exhibited that 3-epicaryoptin halted the MCF-7 cells in the G2/M phase and subsequently induced apoptosis in a time-dependent manner. Our immunofluorescence studies indicated that 3-epicaryoptin inhibited microtubule polymerization in MCF-7 cells. Furthermore, molecular docking followed by molecular dynamics (MD) simulation studies demonstrated the ability of 3-epicaryoptin to interact with the tubulin protein at the colchicine binding pockets. Overall, our results suggest that 3-epicaryoptin can inhibit the proliferation of human breast cancer cells by depolymerizing of cellular microtubule networks, which causes cell cycle arrest and promotes apoptotic cell death. Therefore, it has been indicated that the natural product 3-epicaryoptin exhibited considerable promise as a potent therapeutic agent capable of inducing apoptosis in breast cancer cells.

cancer biology↗

bioRxiv2023

Olfactory system structure and function in newly hatched and adult locusts

An important question in neuroscience is how sensory systems change as animals grow and interact with the environment. Exploring sensory systems in animals as they develop can reveal how networks of neurons process information as the neurons themselves grow and the needs of the animal change. Here we compared the structure and function of peripheral parts of the olfactory pathway in newly hatched and adult locusts. We found that populations of olfactory sensory neurons (OSNs) in hatchlings and adults responded with similar tunings to a panel of odors. The morphologies of local neurons (LNs) and projection neurons (PNs) in the antennal lobes (ALs) were very similar in both age groups, though they were smaller in hatchlings, they were proportional to overall brain size. The odor evoked responses of LNs and PNs were also very similar in both age groups, characterized by complex patterns of activity including oscillatory synchronization. Notably, in hatchlings, spontaneous and odor-evoked firing rates of PNs were lower, and LFP oscillations were lower in frequency, than in the adult. Hatchlings have smaller antennae with fewer OSNs; removing antennal segments from adults also reduced LFP oscillation frequency. Thus, consistent with earlier computational models, the developmental increase in frequency is due to increasing intensity of input to the oscillation circuitry. Overall, our results show that locusts hatch with a fully formed olfactory system that structurally and functionally matches that of the adult, despite its small size and lack of prior experience with olfactory stimuli.

neuroscience↗

bioRxiv2023

Viral protease NIa-Pro increases MEDIATOR SUBUNIT16 cleavage and plant susceptibility to turnip mosaic virus and its aphid vector Myzus persicae.

Plant viruses, such turnip mosaic virus (TuMV), both trigger and inhibit host plant defense responses, including defenses that target their insect vectors, such as aphids. TuMV infection and its protein, NIa-Pro (nuclear inclusion protease a), suppress aphid-induced plant defenses, however the mechanisms of this suppression are still largely unknown. In this study, we determined that NIa-Pros protease activity is required to increase aphid performance on host plants and that 40 transcripts with predicted NIa-Pro cleavage sequences are regulated in Arabidopsis plants challenged with aphids and/or virus compared to healthy controls. One of the candidates, MEDIATOR 16 (MED16), regulates the transcription of ethylene (ET)/jasmonic acid (JA)-dependent defense responses against necrotrophic pathogens. Using immunoblots, mutants, bioassays, and qRT-PCR, we show that a nuclear localization signal is cleaved from MED16 in virus-infected plants and in the presence of NIa-Pro along with the presence of aphids, suggesting MED16 functions in the nucleus may be impacted. Consistent with this, aphid induction of the MED16-dependent transcript of PLANT DEFENSIN 1.2 (PDF1.2), was reduced in virus-infected plants and in plants expressing NIa-Pro compared to controls, and NIa-Pros protease activity was required for this reduction. Finally, we show performance of both the virus and the aphid vector was enhanced on med16 mutant Arabidopsis compared to controls. Overall, this study demonstrates MED16 regulates defense responses against both the virus and the aphid and provides insights into the mechanism by which TuMV suppresses anti-virus and anti-herbivore defenses.

plant biology↗

bioRxiv2023

The ability of the LIMD1 and TRIP6 LIM domains to bind to f-actin under strain is critical for their tension dependent localization to adherens junctions and association with the Hippo pathway kinase LATS1.

A key step in regulation of Hippo pathway signaling in response to mechanical tension is recruitment of the LIM domain proteins TRIP6 and LIMD1 to adherens junctions. Mechanical tension also triggers TRIP6 and LIMD1 to bind and inhibit the Hippo pathway kinase LATS1. How TRIP6 and LIMD1 are recruited to adherens junctions in response to tension is not clear, but previous studies suggested that they could be regulated by the known mechanosensory proteins -catenin and vinculin at adherens junctions. We found that the three LIM domains of TRIP6 and LIMD1 are necessary and sufficient for tension-dependent localization to adherens junctions. The LIM domains of TRIP6, LIMD1, and certain other LIM domain proteins have been shown to bind to actin networks under strain/tension. Consistent with this, we show that TRIP6 and LIMD1 colocalize with the ends of actin fibers at adherens junctions. Point mutations in a key conserved residue in each LIM domain that are predicted to impair binding to f-actin under strain inhibits TRIP6 and LIMD1 localization to adherens junctions and their ability to bind to and recruit LATS1 to adherens junctions. Together these results show that the ability of TRIP6 and LIMD1 to bind to strained actin underlies their ability to localize to adherens junctions and regulate LATS1 in response to mechanical tension.

cell biology↗

bioRxiv2023

The antigenic landscape of human influenza N2 neuraminidases from 2009 until 2017

Human H3N2 influenza viruses are subject to rapid antigenic evolution which translates into frequent updates of the composition of seasonal influenza vaccines. Despite these updates, the effectiveness of influenza vaccines against H3N2-associated disease is suboptimal. Seasonal influenza vaccines primarily induce hemagglutinin-specific antibody responses. However, antibodies directed against influenza neuraminidase (NA) also contribute to protection. Here, we analyzed the antigenic diversity of a panel of N2 NAs derived from human H3N2 viruses that circulated between 2009 and 2017. The antigenic breadth of these NAs was determined based on the NA inhibition (NAI) of a broad panel of ferret and mouse immune sera that were raised by infection and recombinant N2 NA immunization. This assessment allowed us to distinguish at least 4 antigenic groups in the N2 NAs derived from human H3N2 viruses that circulated between 2009 and 2017. Computational analysis further revealed that the amino acid residues in N2 NA that have a major impact on susceptibility to NAI by immune sera are in proximity of the catalytic site. Finally, a machine learning method was developed that allowed to accurately predict the impact of mutations that are present in our N2 NA panel on NAI. These findings have important implications for the renewed interest to develop improved influenza vaccines based on the inclusion of a protective NA antigen formulation.

immunology↗

bioRxiv2023

Dissociation of attentional state and behavioral outcome using local field potentials

Successful behavior depends on attentional state and other factors related to decision-making, which may modulate neuronal activity differently. Here, we investigated whether attentional state and behavioral outcome (i.e., whether a target is detected or missed) are distinguishable using the power and phase of local field potential (LFP) recorded bilaterally from area V4 of monkeys performing a cued visual attention task. To link each trials outcome to pairwise measures of attention that are typically averaged across trials, we used several methods to obtain single-trial estimates of spike count correlation and phase consistency. Surprisingly, while attentional location was best discriminated using gamma and high-gamma power, behavioral outcome was best discriminated by alpha power and steady-state visually evoked potential. Power outperformed absolute phase in attentional/behavioral discriminability, although single-trial gamma phase consistency provided reasonably high attentional discriminability. Our results suggest a dissociation between the neuronal mechanisms that regulate attentional focus and behavioral outcome.

neuroscience↗