Biology subjects

Verschueren, E.

Publications and source records attributed to Verschueren, E..

At least 19 recordsLinked to original sources

bioRxiv2024

Global mapping of the Chlamydia trachomatis conventional secreted effector-host interactome reveals CebN interacts with nucleoporins and Rae1 to impede STAT1 nuclear translocation.

To usurp host defenses and establish a replicative niche, obligate intracellular pathogens are tasked with remodeling the host cell using a comparatively small repertoire of effector proteins. For Chlamydia trachomatis (C.t), discovery of secreted proteins and their host targets has been particularly challenging due to the bacteriums historical genetic intractability. Using affinity purification-mass spectrometry, we defined host interaction partners for 21 secreted effector proteins, providing the first comprehensive type III secretion system (T3SS) effector- host interactome generated during infection. Among these, we show that the C-terminus of CebN (CT584) binds multiple nucleoporins and Rae1, host factors previously associated only with viral immune evasion. Remarkably, we shown that CebN localizes to the nuclear envelope not only in infected cells but also in uninfected bystander cells. Functionally, CebN is both necessary and sufficient to perturb STAT1 nuclear import following IFN-{gamma} stimulation and its expression is critical for C.t. survival, as evidenced by reduced bacterial replication and smaller inclusions in cells infected with a CebN mutant. Together, these finds expand our understanding of chlamydia effector biology and highlight novel bacterial strategies for manipulating host defenses at the nuclear pore. SIGNIFICANCEChlamydia trachomatis (C.t.) is a leading cause of sexually transmitted infections and blindness, yet the molecular mechanisms it uses to manipulate host defenses remain poorly defined. Unlike many pathogens, C.t. relies on a limited set of effectors to remodel the host cell and establish its niche. We identified host targets for 21 C.t. effector proteins. Focusing on CebN, we show that it binds nucleoporins and Rae1, host factors previously linked only to viral immune antagonism. CebN localizes to the nuclear envelope of both infected and bystander cells, and is critical for replication, inclusion development, and perturbation of STAT1 nuclear import following IFN-{gamma} stimulation. These findings uncover a novel strategy by which C.t. manipulates nuclear pore function to evade host defenses and establish infection.

microbiology↗

bioRxiv2023

Targeting the Hippo pathway in cancers via ubiquitination dependent TEAD degradation

The Hippo pathway is among the most frequently altered key signaling pathways in cancer. TEAD1-4 are essential transcription factors and key downstream effectors in the Hippo pathway in human cells. Here, we identified RNF146 as a ubiquitin ligase (E3) of TEADs, which negatively regulates their stability in cells through proteasome-mediated degradation. We show that RNF146-mediated TEAD ubiquitination is dependent on the TEAD PARylation state. We further validated the genetic interaction between RNF146 and the Hippo pathway in cancer cell lines and the model organism Drosophila melanogaster. Despite the RNF146 and proteasome-mediated degradation mechanisms, TEADs are stable proteins with a long half-life in cells. We demonstrate that degradation of TEADs can be greatly enhanced pharmacologically with heterobifunctional chemical inducers of protein degradation (CIDEs). These TEAD-CIDEs can effectively suppress activation of YAP/TAZ target genes in a dose-dependent manner and exhibit significant anti-proliferative effects in YAP/TAZ-dependent tumor cells, thus phenocopying the effect of genetic ablation of TEAD protein. Collectively, this study demonstrates that the ubiquitin-proteasome system plays an important role in regulating TEAD functions and provides a proof-of-concept demonstration that pharmacologically induced TEAD ubiquitination could be leveraged to target YAP/TAZ-driven cancers.

cancer biology↗

bioRxiv2023

Neural envelope tracking predicts speech intelligibility and hearing aid benefit in children with hearing loss

Early assessment of hearing aid benefit is crucial, as the extent to which hearing aids provide audible speech information predicts speech and language outcomes. A growing body of research has proposed neural envelope tracking as an objective measure of speech, particularly for individuals unable to provide reliable behavioral feedback. However, its potential for evaluating speech intelligibility and hearing aid benefit in hearing-impaired children remains unexplored. This study examined neural envelope tracking in hearing-impaired children through two separate experiments. EEG data was recorded while children listened to age-appropriate stories (experiment 1) or an animated movie (experiment 2) under aided and unaided conditions (using personal hearing aids) at multiple stimulus intensities. Results in the delta band demonstrated that neural tracking increased with increasing stimulus intensity, but only in the unaided condition. In the aided condition, neural tracking remained stable across a wide range of intensities, as long as speech intelligibility was maintained. This suggests that acoustic degradation of the speech signal does not necessarily impact neural tracking. Additionally, the use of personal hearing aids significantly enhanced neural envelope tracking, particularly in challenging speech conditions (which would be inaudible when unaided). Furthermore, neural envelope tracking strongly correlated with behaviorally measured speech intelligibility. Altogether, these findings indicate that neural envelope tracking could be a valuable tool for predicting speech intelligibility benefits derived from personal hearing aids in hearing-impaired children. Incorporating narrated stories or engaging movies expands the accessibility of these methods even in clinical settings, offering new avenues for using objective speech measures to guide pediatric audiology decision-making.

neuroscience↗

bioRxiv2023

Delta-band neural envelope tracking predicts speech intelligibility in noise in preschoolers

Behavioral tests are currently the gold standard in measuring speech intelligibility. However, these tests can be difficult to administer in young children due to factors such as motivation, linguistic knowledge and cognitive skills. It has been shown that measures of neural envelope tracking can be used to predict speech intelligibility and overcome these issues. However, its potential as an objective measure for speech intelligibility in noise remains to be investigated in preschool children. Here, we evaluated neural envelope tracking as a function of signal-to-noise ratio (SNR) in 14 5-year-old children. We examined EEG responses to natural, continuous speech presented at different SNRs ranging from -8 (very difficult) to 8 dB SNR (very easy). As expected delta band (0.5-4 Hz) tracking increased with increasing stimulus SNR. However, this increase was not strictly monotonic as neural tracking reached a plateau between 0 and 4 dB SNR, similarly to the behavioral speech intelligibility outcomes. These findings indicate that neural tracking in the delta band remains stable, as long as the acoustical degradation of the speech signal does not reflect significant changes in speech intelligibility. Theta band tracking (4-8 Hz), on the other hand, was found to be drastically reduced and more easily affected by noise in children, making it less reliable as a measure of speech intelligibility. By contrast, neural envelope tracking in the delta band was directly associated with behavioral measures of speech intelligibility. This suggests that neural envelope tracking in the delta band is a valuable tool for evaluating speech-in-noise intelligibility in preschoolers, highlighting its potential as an objective measure of speech in difficult-to-test populations.

neuroscience↗

bioRxiv2022

MSstatsPTM: Statistical relative quantification of post-translational modifications in bottom-up mass spectrometry-based proteomics

Liquid chromatography coupled with bottom up mass spectrometry (LC-MS/MS)-based proteomics is increasingly used to detect changes in post-translational modifications (PTMs) in samples from different conditions. Analysis of data from such experiments faces numerous statistical challenges. These include the low abundance of modified proteoforms, the small number of observed peptides that span modification sites, and confounding between changes in the abundance of PTM and the overall changes in the protein abundance. Therefore, statistical approaches for detecting differential PTM abundance must integrate all the available information pertaining to a PTM site, and consider all the relevant sources of confounding and variation. In this manuscript we propose such a statistical framework, which is versatile, accurate, and leads to reproducible results. The framework requires an experimental design, which quantifies, for each sample, both peptides with post-translational modifications and peptides from the same proteins with no modification sites. The proposed framework supports both label-free and tandem mass tag (TMT)-based LC-MS/MS acquisitions. The statistical methodology separately summarizes the abundances of peptides with and without the modification sites, by fitting separate linear mixed effects models appropriate for the experimental design. Next, model-based inferences regarding the PTM and the protein-level abundances are combined to account for the confounding between these two sources. Evaluations on computer simulations, a spike-in experiment with known ground truth, and three biological experiments with different organisms, modification types and data acquisition types demonstrate the improved fold change estimation and detection of differential PTM abundance, as compared to currently used approaches. The proposed framework is implemented in the free and open-source R/Bioconductor package MSstatsPTM.

bioinformatics↗

bioRxiv2022

Speech understanding oppositely affectsacoustic and linguistic neural tracking in aspeech rate manipulation paradigm.

When listening to continuous speech, the human brain can track features of the presented speech signal. It has been shown that neural tracking of acoustic features is a prerequisite for speech understanding and can predict speech understanding in controlled circumstances. However, the brain also tracks linguistic features of speech, which may be more directly related to speech understanding. We investigated acoustic and linguistic speech processing as a function of varying speech understanding by manipulating the speech rate. In this paradigm, acoustic and linguistic speech processing are affected simultaneously but in opposite directions: When the speech rate increases, more acoustic information per second is present. In contrast, the tracking of linguistic information becomes more challenging when speech is less intelligible at higher speech rates. We measured the EEG of 18 participants (4 male) who listened to speech at various speech rates. As expected and confirmed by the behavioral results, speech understanding decreased with increasing speech rate. Accordingly, linguistic neural tracking decreased with increasing speech rate, but acoustic neural tracking increased. This indicates that neural tracking of linguistic representations can capture the gradual effect of decreasing speech understanding. In addition, increased acoustic neural tracking does not necessarily imply better speech understanding. This suggests that, although more challenging to measure due to the low signal-to-noise ratio, linguistic neural tracking may be a more direct predictor of speech understanding. Significance statementAn increasingly popular method to investigate neural speech processing is to measure neural tracking. Although much research has been done on how the brain tracks acoustic speech features, linguistic speech features have received less attention. In this study, we disentangled acoustic and linguistic characteristics of neural speech tracking via manipulating the speech rate. A proper way of objectively measuring auditory and language processing paves the way towards clinical applications: An objective measure of speech understanding would allow for behavioral-free evaluation of speech understanding, which allows to evaluate hearing loss and adjust hearing aids based on brain responses. This objective measure would benefit populations from whom obtaining behavioral measures may be complex, such as young children or people with cognitive impairments.

neuroscience↗

bioRxiv2020

The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinsons Disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (Tripartite Motif Family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-920, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "Regulatory Loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL serves as a molecular switch controlling LRRK2s association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 modulates LRRK2s interaction with Rab29 and prevents upregulation of LRRK2 kinase activity by Rab29 in an E3-ligase-dependent manner. Finally, TRIM1 rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, controlling its degradation, localization, binding partners, kinase activity, and cytotoxicity.

molecular biology↗

bioRxiv2020

Proteomics of autophagy deficient macrophages reveals enhanced antimicrobial immunity via the oxidative stress response

Defective autophagy is associated with chronic inflammation. Loss-of-function of the core autophagy gene Atg16l1 increases risk for Crohns disease by enhancing innate immunity in macrophages. However, autophagy also mediates clearance of intracellular pathogens. These divergent observations prompted a re-evaluation of ATG16L1 in antimicrobial immunity. In this study, we found that loss of Atg16l1 in macrophages enhanced the killing of virulent Shigella flexneri (S.flexneri), an enteric bacterium that resides within the cytosol by escaping all membrane-bound compartments. Quantitative multiplexed proteomics revealed that ATG16L1 deficiency significantly upregulated proteins involved in the glutathione-mediated antioxidant response to compensate for elevated oxidative stress, which also promoted S.flexneri killing. Consistently, myeloid cell-specific deletion of Atg16l1 accelerated bacterial clearance in vivo. Finally, pharmacological modulation of oxidative stress by suppression of cysteine import conferred enhanced microbicidal properties to wild type macrophages. These findings demonstrate that control of oxidative stress by ATG16L1 regulates antimicrobial immunity against intracellular pathogens. Impact statementMaculins et al utilize multiplexed mass spectrometry to show that loss of the autophagy gene Atg16l1 in macrophages enhances antimicrobial immunity against intracellular pathogens via the oxidative stress response.

cell biology↗

bioRxiv2020

The effect of stimulus intensity on neural envelope tracking

ObjectivesThe last years there has been significant interest in attempting to recover the temporal envelope of a speech signal from the neural response to investigate neural speech processing. The research focus is now broadening from neural speech processing in normal-hearing listeners towards hearing-impaired listeners. When testing hearing-impaired listeners speech has to be amplified to resemble the effect of a hearing aid and compensate peripheral hearing loss. Until today, it is not known with certainty how or if neural speech tracking is influenced by sound amplification. As these higher intensities could influence the outcome, we investigated the influence of stimulus intensity on neural speech tracking. DesignWe recorded the electroencephalogram (EEG) of 20 normal-hearing participants while they listened to a narrated story. The story was presented at intensities from 10 to 80 dB A. To investigate the brain responses, we analyzed neural tracking of the speech envelope by reconstructing the envelope from EEG using a linear decoder and by correlating the reconstructed with the actual envelope. We investigated the delta (0.5-4 Hz) and the theta (4-8 Hz) band for each intensity. We also investigated the latencies and amplitudes of the responses in more detail using temporal response functions which are the estimated linear response functions between the stimulus envelope and the EEG. ResultsNeural envelope tracking is dependent on stimulus intensity in both the TRF and envelope reconstruction analysis. However, provided that the decoder is applied on data of the same stimulus intensity as it was trained on, envelope reconstruction is robust to stimulus intensity. In addition, neural envelope tracking in the delta (but not theta) band seems to relate to speech intelligibility. Similar to the linear decoder analysis, TRF amplitudes and latencies are dependent on stimulus intensity: The amplitude of peak 1 (30-50 ms) increases and the latency of peak 2 (140-160 ms) decreases with increasing stimulus intensity. ConclusionAlthough brain responses are influenced by stimulus intensity, neural envelope tracking is robust to stimulus intensity when using the same intensity to test and train the decoder. Therefore we can assume that intensity is not a confound when testing hearing-impaired participants with amplified speech using the linear decoder approach. In addition, neural envelope tracking in the delta band appears to be correlated with speech intelligibility, showing the potential of neural envelope tracking as an objective measure of speech intelligibility.

neuroscience↗

bioRxiv2020

Fi-score: a novel approach to characterise protein topology and aid in drug discovery studies

Target evaluation is at the centre of rational drug design and biologics development. In order to successfully engineer antibodies, T-cell receptors or small molecules it is necessary to identify and characterise potential binding or contact sites on therapeutically relevant target proteins. Currently, there are numerous challenges in achieving a better docking precision as well as characterising relevant sites. We devised a first-of-its-kind in silico protein fingerprinting approach based on dihedral angle and B-factor distribution to probe binding sites and sites of structural importance. In addition, we showed that the entire protein regions or individual structural subsets can be profiled using our derived fi-score based on amino acid dihedral angle and B-factor distribution. We further described a method to assess the structural profile and extract information on sites of importance using machine learning Gaussian mixture models. In combination, these biophysical analytical methods could potentially help to classify and systematically analyse not only targets but also drug candidates that bind to specific sites which would greatly improve pre-screening stage, target selection and drug repurposing efforts in finding other matching targets.

biophysics↗

bioRxiv2020

Comparative analysis of macrophage post-translational modifications during intracellular bacterial pathogen infection

Macrophages activate robust antimicrobial functions upon engulfing virulent bacteria, yet a wide array of pathogens paradoxically thrive within these innate immune cells. To probe the pathogen-macrophage interface, we used proteomics to comprehensively quantify changes in post-translational modifications (PTMs) of host proteins during infection with three evolutionarily diverse intracellular pathogens: Mycobacterium tuberculosis, Salmonella enterica serovar Typhimurium, and Listeria monocytogenes. Comparing global phosphorylation and ubiquitylation patterns identified extensive reprogramming of cellular pathways during infection, with ubiquitylation patterns revealing unique pathogen-specific molecular response signatures undetectable by transcriptional profiling. Differential PTM changes during infection with attenuated M. tuberculosis cells lacking the ESX-1 virulence determinant revealed extensive modification of phagosome dynamics and antiviral type I interferon activation. We found that M. tuberculosis-mediated activation of the antiviral OASL1-IRF7 pathway promotes bacterial replication, uncovering a new mechanism of virus-bacterial synergy. Our data reveals remarkable specificity in innate cellular responses to complex stimuli and provides a resource for deeper understanding of host-pathogen interactions.

microbiology↗

bioRxiv2020

Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling

Viruses must effectively remodel host cellular pathways to replicate and evade immune defenses, and they must do so with limited genomic coding capacity. Targeting post-translational modification (PTM) pathways provides a mechanism by which viruses can broadly and rapidly transform a hostile host environment into a hospitable one. We used quantitative proteomics to measure changes in two PTM types - phosphorylation and ubiquitination - in response to HIV-1 infection with viruses harboring targeted deletions of a subset of HIV-1 genes. PTM analysis revealed a requirement for Aurora kinase A activity in HIV-1 infection and furthermore revealed that AMP-activated kinase activity is modulated during infection via HIV-1 Vif-mediated degradation of B56-containing protein phosphatase 2A (PP2A). Finally, we demonstrated that the Cullin4A-DDB1-DCAF1 E3 ubiquitin ligase ubiquitinates histone H1 somatic isoforms and that HIV-1 Vpr inhibits this process, leading to defects in DNA repair. Thus, global PTM profiling of infected cells serves as an effective tool for uncovering specific mechanisms of host pathway modulation.

microbiology↗

bioRxiv2019

The Gag Protein PEG10 Binds to RNA and Regulates Trophoblast Stem Cell Lineage Specification.

Peg10 (paternally expressed gene 10) is an imprinted gene that is essential for placental development. It is thought to derive from a Ty3-gyspy LTR (long terminal repeat) retrotransposon and retains Gag and Pol-like domains. Here we show that the Gag domain of PEG10 can promote vesicle budding similar to the HIV p24 Gag protein. Expressed in a subset of mouse endocrine organs in addition to the placenta, PEG10 was identified as a substrate of the deubiquitinating enzyme USP9X. Consistent with PEG10 having a critical role in placental development, PEG10-deficient trophoblast stem cells (TSCs) exhibited impaired differentiation into placental lineages. PEG10 expressed in wild-type, differentiating TSCs was bound to many cellular RNAs including Hbegf (Heparin-binding EGF-like growth factor), which is known to play an important role in placentation. Expression of Hbegf was reduced in PEG10-deficient TSCs suggesting that PEG10 might bind to and stabilize RNAs that are critical for normal placental development.

molecular biology↗

bioRxiv2019

Data-driven spatial filtering for improved measurement of cortical tracking of multiple representations of speech

ObjectiveMeasurement of the cortical tracking of continuous natural speech from electroencephalography (EEG) recordings using a forward model is becoming an important tool in auditory neuroscience. However, it requires a manual channel selection based on visual inspection or prior knowledge to obtain a summary measure of cortical tracking. In this study, we present a method to on the one hand remove non-stimulus-related activity from the EEG signals to be predicted, and on the other hand automatically select the channels of interest. We also aim to show that the EEG prediction from phonology-related speech features is possible in Dutch. ApproachEighteen participants listened to a Flemish story, while their EEG was recorded. Subject-specific and grand-average temporal responses functions were determined between the EEG activity in different frequency bands and several stimulus features: the envelope, spectrogram, phonemes, phonetic features or a combination. The temporal response functions were then used to predict EEG from the stimulus, and the predicted was compared with the recorded EEG, yielding a measure of cortical tracking of stimulus features. A spatial filter was calculated based on the generalized eigenvalue decomposition (GEVD), and the effect on EEG prediction accuracy was determined. Main resultsA model including both low- and high-level speech representations was able to better predict the brain responses to the speech than a model only including low-level features. The inclusion of a GEVD-based spatial filter in the model increased the prediction accuracy of cortical responses to each speech feature at both single-subject (270% improvement) and group-level (310 %). SignificanceWe showed that the inclusion of acoustical and phonetic speech information and the addition of a data-driven spatial filter allow improved modelling of the relationship between the speech and its brain response and offer an automatic channel selection. HighlightsO_LIAutomatic channel selection for evaluating the cortical tracking of continuous natural speech C_LIO_LIData-driven spatial filtering for removing non-stimulus-related activity from the EEG signals C_LIO_LIImproved prediction of brain responses to speech by combining acoustical and phonetic speech information in Dutch C_LI DisclosureThe authors report no disclosures relevant to the manuscript.

neuroscience↗

bioRxiv2018

Predicting individual speech intelligibility from the neural tracking of acoustic- and phonetic-level speech representations

ObjectiveTo objectively measure speech intelligibility of individual subjects from the EEG, based on cortical tracking of different representations of speech: low-level acoustical, higher-level discrete, or a combination. To compare each models prediction of the speech reception threshold (SRT) for each individual with the behaviorally measured SRT.\n\nMethodsNineteen participants listened to Flemish Matrix sentences presented at different signal-to-noise ratios (SNRs), corresponding to different levels of speech understanding. For different EEG frequency bands (delta, theta, alpha, beta or low-gamma), a model was built to predict the EEG signal from various speech representations: envelope, spectrogram, phonemes, phonetic features or a combination of phonetic Features and Spectrogram (FS). The same model was used for all subjects. The model predictions were then compared to the actual EEG of each subject for the different SNRs, and the prediction accuracy in function of SNR was used to predict the SRT.\n\nResultsThe model based on the FS speech representation and the theta EEG band yielded the best SRT predictions, with a difference between the behavioral and objective SRT below 1 decibel for 53% and below 2 decibels for 89% of the subjects.\n\nConclusionA model including low- and higher-level speech features allows to predict the speech reception threshold from the EEG of people listening to natural speech. It has potential applications in diagnostics of the auditory system.\n\nSearch Termscortical speech tracking, objective measure, speech intelligibility, auditory processing, speech representations.\n\nHighlightsO_LIObjective EEG-based measure of speech intelligibility\nC_LIO_LIImproved prediction of speech intelligibility by combining speech representations\nC_LIO_LICortical tracking of speech in the delta EEG band monotonically increased with SNRs\nC_LIO_LICortical responses in the theta EEG band best predicted the speech reception threshold\nC_LI\n\nDisclosureThe authors report no disclosures relevant to the manuscript.

neuroscience↗

bioRxiv2018

Neural envelope tracking as a measure of speech understanding in cochlear implant users

The speech envelope is essential for speech understanding and can be reconstructed from the electroencephalogram (EEG) recorded while listening to running speech. This so-called neural envelope tracking has been shown to relate to speech understanding in normal hearing listeners, but has barely been investigated in persons wearing cochlear implants (CI). We investigated the relation between speech understanding and neural envelope tracking in CI users.\n\nEEG was recorded in 8 CI users while they listened to a story. Speech understanding was varied by changing the intensity of the presented speech. The speech envelope was reconstructed from the EEG using a linear decoder and then correlated with the envelope of the speech stimulus as a measure of neural envelope tracking which was compared to actual speech understanding.\n\nThis study showed that neural envelope tracking increased with increasing speech understanding in every participant. Furthermore behaviorally measured speech understanding was correlated with participant specific neural envelope tracking results indicating the potential of neural envelope tracking as an objective measure of speech understanding in CI users. This could enable objective and automatic fitting of CIs and pave the way towards closed-loop CIs that adjust continuously and automatically to individual CI users.

neuroscience↗

bioRxiv2018

Synthetic essentiality of metabolic regulator PDHK1 in PTEN-deficient cells and cancers

PTEN is a tumor suppressor that is often inactivated in cancer and possesses both lipid and protein phosphatase activities. We report the metabolic regulator PDHK1 (pyruvate dehydrogenase kinase1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The predominant mechanism of PDHK1 regulation and dependency is the PTEN protein phosphatase dephosphorylates NF{kappa};B activating protein (NKAP) and limits NF{kappa}B activation to suppress expression of PDHK1, a NF{kappa}B target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to drive aerobic glycolysis and induce PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, which is a biomarker of decreased patient survival, establishing clinical relevance. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers.\n\nSIGNIFICANCEThe tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. PTEN antagonizes PI3K/AKT signaling via its lipid phosphatase activity. The modest success of PI3K/AKT inhibition in PTEN-deficient cancer patients provides rationale for identifying other vulnerabilities in PTEN-deficient cancers to improve clinical outcomes. We show that PTEN-deficient cells are uniquely sensitive to PDHK1 inhibition. PTEN and PDHK1 co-suppression reduced colony formation and induced cell death in vitro and tumor regression in vivo. PDHK1 levels were high in PTEN-deficient patient tumors and associated with inferior patient survival, establishing clinical relevance. Our study identifies a PTEN-regulated signaling pathway linking the PTEN protein phosphatase to the metabolic regulator PDHK1 and provides a mechanistic basis for PDHK1 targeting in PTEN-deficient cancers.

cancer biology↗

bioRxiv2018

Semantic context enhances neural envelope tracking

ObjectivesRecently an objective measure of speech intelligibility, based on brain responses derived from the electroencephalogram (EEG), has been developed using isolated Matrix sentences as a stimulus. We investigated whether this objective measure of speech intelligibility can also be used with natural speech as a stimulus, as this would be beneficial for clinical applications. DesignWe recorded the EEG in 19 normal-hearing participants while they listened to two types of stimuli: Matrix sentences and a natural story. Each stimulus was presented at different levels of speech intelligibility by adding speech weighted noise. Speech intelligibility was assessed in two ways for both stimuli: (1) behaviorally and (2) objectively by reconstructing the speech envelope from the EEG using a linear decoder and correlating it with the acoustic envelope. We also calculated temporal response functions (TRFs) to investigate the temporal characteristics of the brain responses in the EEG channels covering different brain areas. ResultsFor both stimulus types the correlation between the speech envelope and the reconstructed envelope increased with increasing speech intelligibility. In addition, correlations were higher for the natural story than for the Matrix sentences. Similar to the linear decoder analysis, TRF amplitudes increased with increasing speech intelligibility for both stimuli. Remarkable is that although speech intelligibility remained unchanged in the no noise and +2.5 dB SNR condition, neural speech processing was affected by the addition of this small amount of noise: TRF amplitudes across the entire scalp decreased between 0 to 150 ms, while amplitudes between 150 to 200 ms increased in the presence of noise. TRF latency changes in function of speech intelligibility appeared to be stimulus specific: The latency of the prominent negative peak in the early responses (50-300 ms) increased with increasing speech intelligibility for the Matrix sentences, but remained unchanged for the natural story. ConclusionsThese results show (1) the feasibility of natural speech as a stimulus for the objective measure of speech intelligibility, (2) that neural tracking of speech is enhanced using a natural story compared to Matrix sentences and (3) that noise and the stimulus type can change the temporal characteristics of the brain responses. These results might reflect the integration of incoming acoustic features and top-down information, suggesting that the choice of the stimulus has to be considered based on the intended purpose of the measurement.

neuroscience↗