Biology subjects

Parthasarathy, A.

Publications and source records attributed to Parthasarathy, A..

At least 19 recordsLinked to original sources

bioRxiv2026

A rapid, machine-learning readout of cochlear neural degeneration that transfers from animals to humans

Standard hearing tests miss cochlear neural degeneration (CND), the loss of synapses between inner hair cells and auditory nerve fibers that may underlie unexplained hearing difficulty in roughly one in ten adults. Envelope following responses (EFRs) can index this neural loss noninvasively, but conventional protocols are too slow for clinical use. We tested a dynamic amplitude-modulated (dAM) EFR that sweeps the full modulation spectrum in a single brief stimulus. In Mongolian gerbils with histologically verified CND, dAM EFRs revealed selective deficits at fast modulation rates without threshold elevation. A machine-learning classifier distinguished young from middle-aged animals with high accuracy; additionally, its most informative feature, power near 400-500 Hz, tracked synapse counts, indicating a readout of cochlear neural health rather than age. Applied without retraining to 56 human listeners, the gerbil-trained classifier separated age groups above chance. dAM EFRs thus offer a rapid, objective and clinically viable marker of CND.

neuroscience↗

bioRxiv2026

Distinct Roles of Working Memory and Inhibitory Control in Speech-in-Noise Perception

Difficulty perceiving speech in noise is the primary complaint of patients seeking hearing healthcare, even absent overt losses in audiometric thresholds. Yet current clinical practice largely focuses on sensory function while ignoring the potentially outsized effects of executive function on everyday suprathreshold listening. Speech perception in noise depends on the dynamic interplay between the fidelity of sensory coding along the auditory pathway and higher-order top-down cognitive processes that support goal-directed listening, both of which can independently change across the lifespan. Here we examined how two subcomponents of executive function, working memory and inhibitory control, vary across the adult lifespan and contribute to speech-in-noise performance. Two hundred participants aged 18 to 73 with normal hearing thresholds were tested on a validated online auditory psychophysics platform. Working memory was assessed with an n-back task and inhibitory control with an auditory Stroop task. Participants then performed two speech-in-noise tasks: a modified rhyme test emphasizing sensory coding through energetic masking at the cochlea, and a matrix sentence task emphasizing executive function through informational masking. Age significantly affected performance on both tasks. Aging was associated with reduced inhibitory control (increased Stroop cost) but no significant effect on working memory. Regression analyses revealed that both working memory and inhibitory control predicted performance on the informational masking task, whereas only inhibitory control predicted performance on the energetic masking task. These findings underscore the critical role of executive function in everyday suprathreshold listening and support including cognitive measures in clinical assessments of hearing difficulties.

neuroscience↗

bioRxiv2026

Epithelial and γδ T cell CD47 have complementary yet distinct roles in regulating γδ intraepithelial lymphocyte migration

Intraepithelial lymphocytes expressing the {gamma}{delta} T cell receptor ({gamma}{delta} IEL) continuously survey the intestinal epithelium to promote mucosal host defense. Although {gamma}{delta} IELs migrate in and out of the lateral intercellular space (LIS) between adjacent enterocytes, the molecular mechanisms governing their migratory behavior are incompletely understood. Based on the known role of CD47, or integrin associated protein (IAP), in mediating neutrophil transepithelial migration, we investigated whether CD47 expression reflects a conserved mechanism regulating {gamma}{delta} IEL surveillance behavior. Here, we report that conditional CD47 deletion on intestinal epithelial cells or {gamma}{delta} T cells had no effect on IEL composition. Using intravital imaging, we identified complementary roles for CD47 on {gamma}{delta} IELs and epithelial cells, with epithelial CD47 restricting {gamma}{delta} IEL motility and {gamma}{delta} T-cell-derived CD47 promoting cell migration. Further investigation revealed that both CD47 and CD18 contribute to {gamma}{delta} IEL surveillance behavior, although CD47 regulates {gamma}{delta} IEL migration in a CD18-independent manner.

immunology↗

bioRxiv2026

Central auditory decline precedes cochlear deficits in a D-galactose mimetic model of aging

Age-related hearing loss reflects a mixture of concurrent peripheral cochlear and central auditory pathway degeneration. Disentangling their relative contributions has remained challenging because both decline together with natural aging. Here, we used systemic D-galactose (D-gal) administration to selectively accelerate central auditory aging while preserving peripheral cochlear function. Eight male Fischer 344 rats received daily subcutaneous D-gal injections (500 mg/kg) for eight consecutive weeks. Two-channel auditory evoked potentials, including auditory brainstem responses (ABRs) and envelope-following responses (EFRs), were recorded at three time points: pre-injection, immediately following injections (2 months post), and 12 months post-injection cessation. Two months post-injection, there was a significant reduction in ABR wave amplitudes from central auditory generators (Waves IV and V) and EFRs to slow modulation frequencies ([≤]45 Hz), which reflect midbrain and cortical generators. In contrast, ABR thresholds, wave amplitudes from peripheral generators (Waves I and III), and EFRs to fast modulation rates (>128 Hz) reflecting peripheral neural activity remained unchanged at this time point, indicating preserved cochlear and early brainstem function. Peripheral deficits emerged only by the 12-month follow-up, with elevated thresholds, reduced peripheral wave amplitudes, and reduced EFRs at fast modulation rates. These findings demonstrate a clear temporal dissociation in which central auditory decline precedes peripheral cochlear and neural loss in the D-gal model. This paradigm provides a tractable experimental window for studying mechanisms of central auditory aging in isolation from cochlear pathology, bridging an important gap between peripheral and central models of presbycusis. HighlightsO_LID-galactose accelerates central auditory aging in Fischer 344 rats. C_LIO_LICentral ABR waves and slow EFRs decline within two months of D-gal exposure. C_LIO_LIPeripheral cochlear deficits emerge only after a 12-month delay. C_LIO_LICentral auditory decline precedes cochlear loss in this model. C_LIO_LIProvides a tractable model to study central auditory aging in isolation. C_LI

neuroscience↗

bioRxiv2026

A genome-wide CRISPR screen reveals cancer-specific regulators of hyaluronan binding and cellular invasion

Metastatic spread of cancer cells is driven by binding between the cell-surface receptor CD44 and hyaluronan (HA) in the extracellular matrix. The specific oncogenes that drive increased CD44-HA binding in cancer remain poorly defined. Using a fluorescently labeled hyaluronan probe, we performed a genome-wide CRISPR screen to identify genes whose knockdown disrupts HA binding in breast cancer cells. We subsequently developed a bioinformatic analysis pipeline that enabled stratification and prioritization of cancer-specific regulators. This work provides a first-in-class resource for the identification of druggable targets to inhibit HA binding. We further validate RAB4A, a top hit from our screen, as a novel regulator of this process. Mechanistically, RAB4A KO dramatically reduces CD44 expression and inhibits the invasion of breast cancer cells through HA-rich matrices. This study validates a novel strategy for identifying regulators of cancer cell invasion and identifies immediate actionable targets for anti-metastatic therapy.

cancer biology↗

bioRxiv2025

Degraded neural coding of temporal fine structure with age predicts effortful listening in multi-talker environments

Middle age represents a critical window for early detection of neurophysiological decline. Hearing loss is increasingly recognized as both an early marker of neural degeneration and a modifiable risk factor for dementia. Yet many adults report difficulty understanding speech in noise despite normal audiograms, highlighting the limitations of current clinical tests that fail to capture the underlying physiology or effort required for real-world listening. Beyond hearing thresholds, speech comprehension in complex environments depends on precise neural encoding of temporal fine structure (TFS) cues that convey pitch and spatial information. Here, we use a noninvasive EEG-based measure of neural phase-locking (frequency modulation following responses or FMFRs) to quantify TFS encoding in young and middle-aged adults with normal hearing thresholds. Middle-aged listeners exhibited reduced FMFR amplitudes and shallower discriminability slopes, reflecting diminished neural synchrony despite preserved hearing thresholds. Using a multi-talker speech task we further found that pupil-indexed listening effort was significantly greater in middle-aged adults despite matched accuracy across groups. Further, increases in listening effort were predicted by decreases in TFS encoding. Together, these results reveal that degraded neural encoding of TFS underlies subclinical listening difficulties and increased cognitive load, establishing the FMFR as a sensitive biomarker of hidden auditory neural decline. SignificanceUnderstanding speech in noisy environments depends on precise neural encoding of temporal fine structure (TFS) cues. Using a noninvasive EEG metric, the FMFR, we show that neural TFS coding in the peripheral auditory system declines markedly by midlife, even when hearing thresholds and speech performance are normal. These neural deficits predict elevated pupil-indexed listening effort during multi-talker speech perception, revealing that subclinical degradation of temporal coding increases cognitive load in everyday listening. The FMFR thus provides a promising biomarker for early auditory neural decline and its downstream cognitive consequences.

neuroscience↗

bioRxiv2025

The Slowest Timescales of Neural Synchronization Reveal the Strongest Influence of Auditory Distraction

Among all the sounds occurring at any given time, people are often interested in listening to just one. Some competing sounds are merely background noise, whereas others distract attention from target sounds and are less easily suppressed. During active listening, the central auditory pathway unmixes target and distractor sounds based on temporal differences that vary across three orders of magnitude - from millisecond differences in acoustic temporal fine structure to slower perceptual grouping factors that stretch out to multiple seconds. Here, we developed an approach to directly measure central auditory encoding of multiplexed target and distractor sound features in human listeners to determine which timescales are most impacted by the presence of distracting sounds. Target sounds contained nested features along four timescales, including temporal fine structure ([~]500 Hz), temporal envelope ([~]25-80 Hz), envelope changes ([~]5 Hz), and slower changes in embedded context reflecting whether target stimuli were randomly arranged or formed a repeating pattern ([~]0.5 Hz). Targets were presented with competing sounds that provided variable levels of distraction: either a highly distracting melody or a less distracting noise. Neural synchronization to each timescale was simultaneously and independently measured for target and distractor sounds from electroencephalogram (EEG) recordings during a listening task. Sustained shifts from random to regular arrangements of temporal sequences were reliably perceived, yet did not evoke a pattern recognition potential, nor neural synchronization changes at any timescale. Synchronization to relatively slow changes in envelope transitions (<10Hz) of the target sound deteriorated with the addition of a more distracting sound while synchronization to more rapid fluctuations in the fine structure or envelope modulation rate were unaffected by varying levels of distraction. Categorizing trials according to task performance revealed a conjunction of enhanced entrainment to slower temporal features in the distractor sound and reduced synchronization to the target sound on error trials. By designing a stimulus paradigm that leveraged the remarkable temporal processing capabilities of the auditory nervous system, we were able to simultaneously quantify multiple target and distractor sound features reproduced in the EEG. This paradigm identified synchronization processes in the 7-10 Hz alpha range that has been linked to distractor suppression, which may prove valuable for research on clinical populations who report difficulty suppressing awareness of distracting sounds.

neuroscience↗

bioRxiv2024

A novel mechanism for the uptake of enterobactin-chelated ferric ions by the mitochondria and subsequent reduction to ferrous ions inside

Conventional knowledge of mitochondrial iron metabolism talks about the export of iron in its doubly charged state once it is reduced inside the cell until it reaches the mitochondria. At physiological oxygen tension and pH 7.4, the comparatively soluble Fe(II) is easily available. Fe(III) hydrolyses to generate insoluble ferric hydroxides. Iron must be regularly chaperoned because of its near insolubility and potential toxicity due to redox activity. All tissues pick up iron through the binding of transferrin (Tf) to the transferrin receptor 1 (TfR1), followed by the complexs internalisation through receptor-mediated endocytosis. The low pH created by the operation of a proton pump within the endosome reduces Tfs affinity for iron. Importantly, the TfR1 promotes iron escape from Tf in the pH range (pH 5-5.5) reached by the endosome. A "trap," such as pyrophosphate, is needed in vitro for iron release from Tf. However, a physiological chelator that can play this role has not yet been discovered. Fe(III) is hypothesised to be reduced to Fe(II) in erythroid cells by a ferrireductase known as the six-transmembrane epithelial antigen of the prostate 3 in the endosomal membrane after being released from Tf in the endosome. Following this, the divalent metal transporter-1 (DMT1) transports Fe(II) through the endosomal membrane and, it is generally accepted that this generates the cytosolic labile or chelatable iron pool. This reservoir of iron is believed to provide the metal for metabolic requirements, including as iron intake by the mitochondrion for haem and ISC synthesis, as well as storage in the cytosolic protein ferritin. The possibility of Fe(III) entering the mitochondria has not been explored before. A series of dockings shows that binding of the alpha subunit to a complex of Fe(III) with enterobactin is as stable as the binding with of the same chelator with Fe(II). Enterobactin is a bacterial iron chelator thought to play an integral role in host iron metabolism. Our results suggest an interesting possibility of iron being trafficked to the mitochondria as Fe(III). We propose a potential mechanism of Fe(III) trafficking and subsequent reduction to Fe(II) inside the mitochondria.

biochemistry↗

bioRxiv2024

Reduced neural distinctiveness of speech representations in the middle-aged brain

Speech perception declines independent of hearing thresholds in middle-age, and the neurobiological reasons are unclear. In line with the age-related neural dedifferentiation hypothesis, we predicted that middle-aged adults show less distinct cortical representations of phonemes and acoustic-phonetic features relative to younger adults. In addition to an extensive audiological, auditory electrophysiological, and speech perceptual test battery, we measured electroencephalographic responses time-locked to phoneme instances (phoneme-related potential; PRP) in naturalistic, continuous speech and trained neural network classifiers to predict phonemes from these responses. Consistent with age-related neural dedifferentiation, phoneme predictions were less accurate, more uncertain, and involved a broader network for middle-aged adults compared with younger adults. Representational similarity analysis revealed that the featural relationship between phonemes was less robust in middle-age. Electrophysiological and behavioral measures revealed signatures of cochlear neural degeneration (CND) and speech perceptual deficits in middle-aged adults relative to younger adults. Consistent with prior work in animal models, signatures of CND were associated with greater cortical dedifferentiation, explaining nearly a third of the variance in PRP prediction accuracy together with measures of acoustic neural processing. Notably, even after controlling for CND signatures and acoustic processing abilities, age-group differences in PRP prediction accuracy remained. Overall, our results reveal "fuzzier" phonemic representations, suggesting that age-related cortical neural dedifferentiation can occur even in middle-age and may underlie speech perceptual challenges, despite a normal audiogram.

neuroscience↗

bioRxiv2024

Increased listening effort and cochlear neural degeneration underlie behavioral deficits in speech perception in noise in normal hearing middle-aged adults.

Middle age represents a critical period of accelerated brain changes and provides a window for early detection and intervention in age-related neurological decline. Hearing loss is a key early marker of such decline and is linked to numerous comorbidities in older adults. Yet, [~]10% of middle-aged individuals who report hearing difficulties show normal audiograms. Cochlear neural degeneration (CND) could contribute to these hidden hearing deficits, though its role remains unclear due to a lack of objective diagnostics and uncertainty regarding its perceptual outcomes. Here, we employed a cross-species design to examine neural and behavioral signatures of CND. We measured envelope following responses (EFRs) - neural ensemble responses to sound originating from the peripheral auditory pathway - in young and middle-aged adults with normal audiograms and compared these responses to young and middle-aged Mongolian gerbils, where CND was histologically confirmed. We observed near identical changes in EFRs across species that were associated with CND. Behavioral assessments revealed agerelated speech-in-noise deficits under challenging conditions, while pupil-indexed listening effort increased with age even when behavioral performance was matched. Together, these results demonstrate that CND contributes to speech perception difficulties and elevated listening effort in midlife, which may ultimately lead to listening fatigue and social withdrawal.

neuroscience↗

bioRxiv2024

Rapid and objective assessment of auditory temporal processing using dynamic amplitude-modulated stimuli

Auditory neural coding of speech-relevant temporal cues can be noninvasively probed using envelope following responses (EFRs), neural ensemble responses phase-locked to the stimulus amplitude envelope. EFRs emphasize different neural generators, such as the auditory brainstem or auditory cortex, by altering the temporal modulation rate of the stimulus. EFRs can be an important diagnostic tool to assess auditory neural coding deficits that go beyond traditional audiometric estimations. Existing approaches to measure EFRs use discrete amplitude modulated (AM) tones of varying modulation frequencies, which is time consuming and inefficient, impeding clinical translation. Here we present a faster and more efficient framework to measure EFRs across a range of AM frequencies using stimuli that dynamically vary in modulation rates, combined with spectrally specific analyses that offer optimal spectrotemporal resolution. EFRs obtained from several species (humans, Mongolian gerbils, Fischer-344 rats, and Cba/CaJ mice) showed robust, high-SNR tracking of dynamic AM trajectories (up to 800Hz in humans, and 1.4 kHz in rodents), with a fivefold decrease in recording time and thirtyfold increase in spectrotemporal resolution. EFR amplitudes between dynamic AM stimuli and traditional discrete AM tokens within the same subjects were highly correlated (94% variance explained) across species. Hence, we establish a time-efficient and spectrally specific approach to measure EFRs. These results could yield novel clinical diagnostics for precision audiology approaches by enabling rapid, objective assessment of temporal processing along the entire auditory neuraxis.

neuroscience↗

bioRxiv2023

Sensory representations and pupil-indexed listening effort provide complementary contributions to multi-talker speech intelligibility

Optimal speech perception in noise requires successful separation of the target speech stream from multiple competing background speech streams. The ability to segregate these competing speech streams depends on the fidelity of bottom-up neural representations of sensory information in the auditory system and top-down influences of effortful listening. Here, we use objective neurophysiological measures of bottom-up temporal processing using envelope-following responses (EFRs) to amplitude modulated tones and investigate their interactions with pupil-indexed listening effort, as it relates to performance on the Quick speech in noise (QuickSIN) test in young adult listeners with clinically normal hearing thresholds. We developed an approach using ear-canal electrodes and adjusting electrode montages for modulation rate ranges, which extended the rage of reliable EFR measurements as high as 1024Hz. Pupillary responses revealed changes in listening effort at the two most difficult signal-to-noise ratios (SNR), but behavioral deficits at the hardest SNR only. Neither pupil-indexed listening effort nor the slope of the EFR decay function independently related to QuickSIN performance. However, a linear model using the combination of EFRs and pupil metrics significantly explained variance in QuickSIN performance. These results suggest a synergistic interaction between bottom-up sensory coding and top-down measures of listening effort as it relates to speech perception in noise. These findings can inform the development of next-generation tests for hearing deficits in listeners with normal-hearing thresholds that incorporates a multi-dimensional approach to understanding speech intelligibility deficits.

physiology↗

bioRxiv2023

Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice

BACKGROUNDOncolytic adenoviruses, such as Delta-24-RGD, show promise as a potential breakthrough in treating patients with high-grade gliomas. However, their effectiveness against gliomas can be hindered by the presence of neutralizing antibodies. METHODSProduction of human neutralizing antibodies against adenoviruses was assessed in two cohorts of patients with malignant gliomas treated with Delta-24-RGD in a phase 1 clinical trial. Sera containing neutralizing antibodies were also obtained from mice immunized with intramuscular injections of wild-type Ad5. Chimeric adenovirus was constructed using molecular cloning, and its activity was assessed in vitro using quantitative PCR, western blot, and transmission electron microscopy. The therapeutic efficacy of the chimeric virus was tested in vivo using sera from patients previously treated with Delta-24-RGD and immunocompetent murine models of glioma. RESULTSExamination of sera from patients with malignant gliomas treated with Delta-24-RGD revealed that in the cohort treated with multiple injections of this oncolytic adenovirus, a higher percentage of patients developed neutralizing antibodies when compared to the patients treated with a single injection of Delta-24-RGD. Of note, long-term survival was only observed in patients who received a single injection. Delta-24-RGD-H43m, a chimeric oncolytic adenovirus engineered to overcome virus neutralization, demonstrated a potent anti-glioma effect both in vitro and in vivo. This chimeric virus showed resilience against anti-Ad5 neutralizing antibodies and conferred better therapeutic efficacy compared to Delta-24-RGD in mice with immunity against Ad5. Of further clinical relevance, Delta-24-RGD-H43m also evaded the inhibitory effects of sera from human patients treated with Delta-24-RGD. CONCLUSIONSThe development of neutralizing antibodies due to multiple virus injections was associated with lower frequency of long-term survivors in a clinical trial. The new chimeric virus shows increased resilience to inactivation by the sera of human patients compared to the parental virus. These findings lay the foundation for a novel oncolytic virus treatment approach targeting a significant percentage of glioma patients with prior exposure to adenovirus.

cancer biology↗

bioRxiv2022

Unraveling the therapeutic mechanism of deep-brain stimulation

Deep-brain stimulation (DBS) is an effective treatment for patients suffering from otherwise therapy-resistant psychiatric disorders, including obsessive-compulsive disorder. Modulation of cortico-striatal circuits has been suggested as a mechanism of action. To gain mechanistic insight, we monitored neuronal activity in cortico-striatal regions in a mouse model for compulsive behavior, while systematically varying clinically-relevant parameters of internal-capsule DBS. DBS showed dose-dependent effects on both brain and behavior: An increasing, yet balanced, number of excited and inhibited neurons was recruited, scattered throughout cortico-striatal regions, while compulsive grooming decreased. Such neuronal recruitment did not alter basic brain function such as resting-state activity, and only occurred in awake animals, indicating a dependency on network activity. In addition to these widespread effects, we observed specific involvement of the medial orbitofrontal cortex in therapeutic outcomes, which was corroborated by optogenetic stimulation. Together, our findings provide mechanistic insight into how DBS exerts its therapeutic effects on compulsive behaviors.

neuroscience↗

bioRxiv2022

Neural signatures of auditory hypersensitivity following acoustic trauma

Throughout the brain, neurons exhibit a remarkable capacity to maintain stable firing rates despite large perturbations in afferent activity levels. As an exception, homeostatic regulation of neural activity often fails in the adult auditory system after hearing loss. Cochlear deafferentation caused by aging or noise exposure triggers widespread neural hyperactivity, particularly in the auditory cortex (ACtx), which underlies perceptual disorders including tinnitus and hyperacusis. Here, we show that mice with noise-induced damage of the high-frequency cochlear base were behaviorally hypersensitive to spared mid-frequency tones and to direct optogenetic stimulation of auditory thalamocortical neurons. Chronic 2-photon calcium imaging from ACtx pyramidal neurons (PyrNs) revealed an initial stage of diffuse hyperactivity, hypercorrelation, and hyperresponsivity that consolidated around deafferented map regions three or more days after acoustic trauma. Deafferented PyrN ensembles displayed hypersensitive decoding of spared mid-frequency tones, mirroring behavioral hypersensitivity. At the level of individual PyrNs, some exhibited stable, homeostatic gain control after acoustic trauma, while others showed non-homeostatic excess gain. Interestingly, factors such as baseline spontaneous activity levels and sound level encoding could account for 40% of the variability in PyrN gain regulation after acoustic trauma. These findings suggest that non-homeostatic regulation of cortical sound intensity coding following sensorineural loss may underlie the well-established clinical phenomenon of loudness hypersensitivity. Further, while cortical gain changes are triggered by reduced bottom-up afferent input, their subsequent stabilization is also shaped by their local circuit milieu, where baseline response features can identify neurons with the greatest propensity for developing pathological hyperactivity following sensorineural hearing loss.

neuroscience↗

bioRxiv2021

Pyruvate oxidase as a key determinant of pneumococcal viability during transcytosis across the blood-brain barrier endothelium

Streptococcus pneumoniae (SPN / pneumococcus), invades myriad of host tissues following efficient breaching of cellular barriers. However, strategies adopted by pneumococcus for evasion of host intracellular defences governing successful transcytosis across host cellular barriers remain elusive. In this study, using brain endothelium as a model host barrier, we observed that pneumococcus containing endocytic vacuoles (PCVs) formed following SPN internalization into brain microvascular endothelial cells (BMECs), undergo early maturation and acidification, with a major subset acquiring lysosome-like characteristics. Exploration of measures that would preserve pneumococcal viability in the lethal acidic pH of these lysosome-like vacuoles revealed a critical role of the two-component system response regulator, CiaR, which has been previously implicated in induction of acid tolerance response. Pyruvate oxidase (SpxB), a key sugar metabolizing enzyme that catalyses oxidative decarboxylation of pyruvate to acetyl phosphate, was found to contribute to acid stress tolerance, presumably via acetyl phosphate-mediated phosphorylation and activation of CiaR, independent of its cognate kinase CiaH. Hydrogen peroxide, the by-product of SpxB catalysed reaction, was also found to improve pneumococcal intracellular survival, by oxidative inactivation of lysosomal cysteine cathepsins, thus compromising the degradative capacity of the host lysosomes. Expectedly, a {Delta}spxB mutant was found to be significantly attenuated in its ability to survive inside the BMEC endocytic vacuoles, reflecting in its reduced transcytosis ability. Collectively, our studies establish SpxB as an important virulence determinant facilitating pneumococcal survival inside host cells, ensuring successful trafficking across host cellular barriers. AUTHOR SUMMARYEukaryotic cells which constitute host barriers have innate immune defences to restrict microbial passage into sterile compartments. This necessitates need for pathogens to devise strategies to evade these, for successful establishment of disease. In this study, by focussing on the blood-brain barrier endothelium, we investigate the mechanisms which enable the opportunistic pathogen Streptococcus pneumoniae to traverse host barriers. Pyruvate oxidase, a pneumococcal sugar metabolizing enzyme was found to play a critical role in this key event, owing to production of acetyl phosphate and hydrogen peroxide via its enzymatic activity. On one hand, acetyl phosphate, by contributing to activation of acid tolerance stress response, enabled pneumococci to maintain viability in the lethal acidic pH of the lysosome-like vacuoles inside brain endothelium. On the other, hydrogen peroxide, was found to oxidise and inactivate a subset of degradative lysosomal enzymes. This two-pronged approach, aided by pyruvate oxidase, enabled pneumococci to evade intracellular degradation for successful transcytosis across the endothelium. Thus, pyruvate oxidase is a key determinant of pneumococcal virulence and hence can potentially serve as a viable candidate for therapeutic interventions for better management of invasive pneumococcal diseases.

microbiology↗

bioRxiv2019

Independent Activity Subspaces for Working Memory and Motor Preparation in the Lateral Prefrontal Cortex

The lateral prefrontal cortex is involved in the integration of multiple types of information, including working memory and motor preparation. However, it is not known how downstream regions can extract one type of information without interference from the others present in the network. Here we show that the lateral prefrontal cortex contains two independent low-dimensional subspaces: one that encodes working memory information, and another that encodes motor preparation information. These subspaces capture all the information about the target in the delay periods, and the information in both subspaces is reduced in error trials. A single population of neurons with mixed selectivity forms both subspaces, but the information is kept largely independent from each other. A bump attractor model with divisive normalization replicates the properties of the neural data. These results have implications for the neural mechanisms of cognitive flexibility and capacity limitations.

neuroscience↗

bioRxiv2019

Neural signatures of disordered multi-talker speech perception in adults with normal hearing

In social settings, speech waveforms from nearby speakers mix together in our ear canals. The brain unmixes the attended speech stream from the chorus of background speakers using a combination of fast temporal processing and cognitive active listening mechanisms. Multi-talker speech perception is vulnerable to aging or auditory abuse. We found that [~]10% of adult visitors to our clinic have no measurable hearing loss, yet offer a primary complaint of poor hearing. Multi-talker speech intelligibility in these adults was strongly correlated with neural phase locking to frequency modulation (FM) cues, as determined from ear canal EEG recordings. Combining neural temporal fine structure (TFS) processing with pupil-indexed measures of cognitive listening effort could predict most of the individual variance in speech intelligibility thresholds. These findings identify a confluence of disordered bottom-up and top-down processes that predict poor multi-talker speech perception and could be useful in next-generation tests of hidden hearing disorders.

neuroscience↗