Biology subjects

Gross, J.

Publications and source records attributed to Gross, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2020

Culture volume influences the dynamics of adaptation under long-term stationary phase

Escherichia coli and many other bacterial species, which are incapable of sporulation, can nevertheless survive within resource exhausted media by entering a state termed long-term stationary phase (LTSP). We have previously shown that E. coli populations adapt genetically under LTSP in an extremely convergent manner. Here we examine how the dynamics of LTSP genetic adaptation are influenced by varying a single parameter of the experiment - culture volume. We find that culture volume affects survival under LTSP, with viable counts decreasing as volumes increase. Across all volumes, mutations accumulate with time, and the majority of mutations accumulated demonstrate signals of being adaptive. However, positive selection appears to affect mutation accumulation more strongly at higher, compared to lower volumes. Finally, we find that several similar genes are likely involved in adaptation across volumes. However, the specific mutations within these genes that contribute to adaptation can vary in a consistent manner. Combined, our results demonstrate how varying a single parameter of an evolutionary experiment can substantially influence the dynamics of observed adaptation.

evolutionary biology↗

bioRxiv2020

Dynamics of mutation accumulation and adaptation during three years of evolution under long-term stationary phase

Many bacterial species that cannot sporulate, such as the model bacterium Escherichia coli, can nevertheless survive for years under resource exhaustion, in a state termed long-term stationary phase (LTSP). Here we describe the dynamics of E. coli adaptation during the first three years spent under LTSP. We show that during this time E. coli continuously adapts genetically, through the accumulation of mutations. For non-mutator clones, the majority of mutations accumulated appear to be adaptive under LTSP, reflected in an extremely convergent pattern of mutation accumulation. Despite the rapid and convergent manner in which populations adapt under LTSP, they continue to harbor extensive genetic variation. The dynamics of evolution of mutation rates under LTSP are particularly interesting. The emergence of mutators, affects overall mutation accumulation rates as well as the mutational spectra and the ultimate spectrum of adaptive alleles acquired under LTSP. With time, mutators can evolve even higher mutation rates, through the acquisition of additional mutation-rate enhancing mutations. Different mutator and non-mutator clones within a single population and time point can display extreme variation in their mutation rates, resulting in differences in both the dynamics of adaptation and their associated deleterious burdens. Despite these differences, clones that vary greatly in their mutation rates tend to co-exist within their populations for many years, under LTSP.

evolutionary biology↗

bioRxiv2020

Respiration modulates oscillatory neural network activity at rest

Despite recent advances in understanding how respiration affects neural signalling to influence perception, cognition, and behaviour, it is yet unclear to what extent breathing modulates brain oscillations at rest. We acquired respiration and resting state magnetoencephalography (MEG) data from human participants to investigate if, where, and how respiration cyclically modulates oscillatory amplitudes (2 - 150 Hz). Using measures of phase-amplitude coupling, we show respiration-modulated brain oscillations (RMBOs) across all major frequency bands. Sources of these modulations spanned a widespread network of cortical and subcortical brain areas with distinct spectro-temporal modulation profiles. Globally, high-frequency gamma modulation increased with distance to the head centre, whereas delta and theta modulation decreased with height in the sagittal plane. Overall, we provide the first comprehensive mapping of RMBOs across the entire brain, highlighting respiration-brain coupling as a fundamental mechanism to shape neural processing within canonical resting-state and respiratory control networks.

neuroscience↗

bioRxiv2020

DNA methyltransferase 1 (DNMT1) function is implicated in the age-related loss of cortical interneurons

Increased life expectancy in modern society comes at the cost of age-associated disabilities and diseases. Aged brains not only show reduced excitability and plasticity, but also a decline in inhibition. Age-associated defects in inhibitory circuits likely contribute to cognitive decline and age-related disorders. Molecular mechanisms that exert epigenetic control of gene expression, contribute to age-associated neuronal impairments. Both DNA methylation, mediated by DNA methyltransferases (DNMTs), and histone modifications maintain neuronal function throughout lifespan. Here we provide evidence that DNMT1 function is implicated in the age-related loss of cortical inhibitory interneurons. Deletion of Dnmt1 in parvalbumin-positive interneurons attenuates their age-related decline in the cerebral cortex. Moreover, DNMT1-deficient mice show improved somatomotor performance and reduced aging-associated transcriptional changes. A decline in the proteostasis network, responsible for the proper degradation and removal of defective proteins, is suggested to be essentially implicated in age- and disease-related neurodegeneration. Our data suggest that DNMT1 acts indirectly on interneuron survival in aged mice by modulating the proteostasis network during life-time.

neuroscience↗

bioRxiv2020

Investigating the neuronal oscillatory correlates of the Gratton effect

Rhythmic brain activity may provide a functional mechanism that facilitates dynamic interareal interactions and thereby give rise to complex behavior. It has been shown that low and high frequency oscillations propagate in opposite directions, but interactions between brain areas in various frequency bands are poorly understood. We investigated local and long-range synchrony in a brain-wide network and their relation to behavior, while human subjects executed a variant of the Simon task during MEG recording. We hypothesized that the behavioral difference for stimulus-response congruent (C) and incongruent (IC) trials is caused by differences in cortical synchrony, and that the relative behavioral benefit for trials following instances with the same stimulus-response contingency (i.e. the Gratton effect) is caused by contingency-induced changes in the state of the network. This would be achieved by temporarily upregulating the connectivity strength between behaviorally relevant network nodes. We identified regions-of-interest that differed in local synchrony during the response phase of the Simon task. Within this network, spectral power in none of the nodes in either of the studied frequencies was significantly different in the pre-cue window of the subsequent trial. Nor was there a significant difference in coherence between the task-relevant nodes that could explain the superior performance after compatible consecutive trials.

neuroscience↗

bioRxiv2020

Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates

The induction of broad and potent immunity by vaccines is the key focus of research efforts aimed at protecting against HIV-1 infection. Soluble native-like HIV-1 envelope glycoproteins have shown promise as vaccine candidates as they can induce potent autologous neutralizing responses in rabbits and non-human primates. In this study, monoclonal antibodies were isolated and characterized from rhesus macaques immunized with the BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies reveal a diverse landscape of antibodies recognizing immunodominant strain-specific epitopes and non-neutralizing neo-epitopes. Additionally, we isolated a subset of mAbs against an epitope cluster at the gp120-gp41 interface that recognize the highly conserved fusion peptide and the glycan at position 88 and have characteristics akin to several human-derived broadly neutralizing antibodies.

immunology↗

bioRxiv2020

dnmt1 function is required to maintain retinal stem cells within the ciliary marginal zone of the zebrafish eye

The ciliary marginal zone (CMZ) of the zebrafish retina contains a population of actively proliferating resident stem cells, which generate retinal neurons throughout life. The maintenance methyltransferase, dnmt1, is expressed within the CMZ. Loss of dnmt1 function results in gene misregulation and cell death in a variety of developmental contexts, however, its role in retinal stem cell (RSC) maintenance is currently unknown. Here, we demonstrate that zebrafish dnmt1s872 mutants possess severe defects in RSC maintenance within the CMZ. Using a combination of immunohistochemistry, in situ hybridization, and a transgenic reporter assay, our results demonstrate a requirement for dnmt1 activity in the regulation of RSC proliferation, gene expression and in the repression of endogenous retroelements (REs). Ultimately, cell death is elevated in the dnmt1-/- CMZ, but in a p53-independent manner. Using a transgenic reporter for RE transposition activity, we demonstrate increased transposition in the dnmt1-/- CMZ. Taken together our data identify a critical role for dnmt1 function in RSC maintenance in the vertebrate eye.

developmental biology↗

bioRxiv2020

Cortical tracking of speech in noise accounts for reading strategies in children

Humans propensity to acquire literacy relates to several factors, among which, the ability to understand speech in noise (SiN). Still, the nature of the relation between reading and SiN perception abilities remains poorly understood. Here, we dissect the interplay between (i) reading abilities, (ii) classical behavioral predictors of reading (phonological awareness, phonological memory and lexical access), and (iii) electrophysiological markers of SiN perception in 99 elementary school children (26 with dyslexia). We demonstrate that cortical representation of phrasal content of SiN relates to the development of the lexical (but not sublexical) reading strategy. In contrast, classical behavioral predictors of reading abilities and the ability to benefit from visual speech to represent the syllabic content of SiN account for global reading performance (i.e., speed and accuracy of lexical and sublexical reading). Finally, we found that individuals with dyslexia properly integrate visual speech information to optimize processing of syntactic information, but not to sustain acoustic/phonemic processing. These results clarify the nature of the relation between SiN perception and reading abilities in typical and dyslexic child readers, and identified novel electrophysiological markers of emergent literacy.

neuroscience↗

bioRxiv2020

Tidal volume and respiration phase modulate cortico-muscular communication

Recent studies in animals have convincingly demonstrated that respiration cyclically modulates oscillatory neural activity across diverse brain areas. To what extent this generalises to humans in a way that is relevant for behaviour is yet unclear. We used magnetoencephalography (MEG) to assess the potential influence of tidal volume and respiration phase on the human motor system. We obtained simultaneous recordings of brain activity, muscle activity, and respiration while participants performed an isometric contraction task. We used corticomuscular coherence as a measure of efficient long-range cortico-peripheral communication. We found coherence within the beta range over sensorimotor cortex to be reduced during voluntary deep compared to involuntary normal breathing. Moreover, beta coherence was found to be cyclically modulated by respiration phase in both conditions. Overall, these results demonstrate how respiratory rhythms actively influence brain oscillations in an effort to synchronise neural activity for the sake of computational efficiency. Intriguing questions remain with regard to the shape of these modulatory processes and how they influence perception, cognition, and behaviour.

neuroscience↗

bioRxiv2019

Mitf-family transcription factor function is required within cranial neural crest cells to promote choroid fissure closure

A critical step in eye development is closure of the choroid fissure (CF), a transient structure in the ventral optic cup through which vasculature enters the eye and ganglion cell axons exit. While many factors have been identified that function during CF closure, the molecular and cellular mechanisms mediating this process remain poorly understood. Failure of CF closure results in colobomas. Recently, MITF was shown to be mutated in a subset of human coloboma patients, but how MITF functions during CF closure is unknown. To address this question, zebrafish with mutations in mitfa and tfec, two members of the Mitf-family of transcription factors, were analyzed and their functions during CF closure determined. mitfa;tfec mutants possess severe colobomas and our data demonstrate that Mitf activity is required within cranial neural crest cells (cNCCs) to facilitate CF closure. In the absence of Mitf function, cNCC migration and localization in the optic cup are perturbed. These data shed light on the cellular mechanisms underlying colobomas in patients with MITF mutations and identify a novel role for Mitf function in cNCCs during CF closure. Summary StatementMitf-family transcription factors act within cranial neural crest cells to promote choroid fissure closure. Without Mitf-family function, cNCC localization and function in the CF is disrupted, thus contributing to colobomas.

developmental biology↗

bioRxiv2019

The frequency gradient of human resting-state brain oscillations follows cortical hierarchies

The human cortex is characterized by local morphological features such as cortical thickness, myelin content and gene expression that change along the posterior-anterior axis. We investigated if these structural gradients are associated with a similar gradient in a prominent feature of brain activity - namely the frequency of brain oscillations. In resting-state MEG recordings from healthy participants (N=187), we found that the strongest peak frequency in a brain area decreases significantly, gradually and robustly along the posterior-anterior axis following the global hierarchy from early sensory to higher-order areas. This spatial gradient of peak frequency was significantly anticorrelated with the cortical thickness of corresponding areas representing a proxy of the cortical hierarchical level. This result indicates that the intrinsic resonance frequency decreases systematically from early sensory to higher-order areas and establishes a new structure-function relationship pertaining to brain oscillations as a core organizational principle that may underlie hierarchical specialization in the brain.

neuroscience↗

bioRxiv2019

Spatial attention enhances cortical tracking of quasi-rhythmic visual stimuli

Successfully interpreting and navigating our natural visual environment requires us to track its dynamics constantly. Additionally, we focus our attention on behaviorally relevant stimuli to enhance their neural processing. Little is known, however, about how sustained attention affects the ongoing tracking of stimuli with rich natural temporal dynamics. Here, we used MRI-informed source reconstructions of magnetoencephalography (MEG) data to map to what extent various cortical areas track concurrent continuous quasi-rhythmic visual stimulation. Further, we tested how top-down visuo-spatial attention influences this tracking process. Our bilaterally presented quasi-rhythmic stimuli covered a dynamic range of 4 - 20Hz, subdivided into three distinct bands. As an experimental control, we also included strictly rhythmic stimulation (10 vs 12 Hz). Using a spectral measure of brain-stimulus coupling, we were able to track the neural processing of left vs. right stimuli independently, even while fluctuating within the same frequency range. The fidelity of neural tracking depended on the stimulation frequencies, decreasing for higher frequency bands. Both attended and non-attended stimuli were tracked beyond early visual cortices, in ventral and dorsal streams depending on the stimulus frequency. In general, tracking improved with the deployment of visuo-spatial attention to the stimulus location. Our results provide new insights into how human visual cortices process concurrent dynamic stimuli and provide a potential mechanism - namely increasing the temporal precision of tracking - for boosting the neural representation of attended input.

neuroscience↗

bioRxiv2019

Largely distinct networks mediate perceptually-relevant auditory and visual speech representations

Visual speech is an integral part of communication, but it remains unclear whether information carried by lip movements is represented in the same brain regions that mediate acoustic speech comprehension. Our ability to understand acoustic speech seems independent from that to understand visual speech, yet neuroimaging studies suggest that the neural representations largely overlap. Addressing this discrepancy, we tested where the brain represents acoustically and visually conveyed word identities in a full-brain MEG study. Our analyses dissociate cerebral representations that merely reflect the physical stimulus from those that also predict comprehension, and suggest that these overlap only in specific temporal and frontal regions. Moreover, representations predictive of auditory and visual comprehension converge only in angular and inferior frontal regions. These results provide a neural explanation for the behavioural dissociation of acoustic and visual speech comprehension and suggest that cerebral representations encoding word identities may be more modality-specific than often upheld.

neuroscience↗

bioRxiv2019

Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically and comprehensively exploited the potential of electroencephalography (EEG) to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4 - 8 Hz) and gamma (> 60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results implicate increased theta and gamma synchrony in frontal brain areas in the pathophysiology of chronic pain. While substantial challenges concerning accuracy, specificity and validity of potential EEG-based disease markers remain to be overcome, our study identifies abnormal frontal synchrony at theta and gamma frequencies as promising targets for non-invasive brain stimulation and/or neurofeedback approaches.

neuroscience↗

bioRxiv2018

Conformational dynamics of the HIV Vif protein complex

HIV-1 viral infectivity factor (Vif) is an intrinsically disordered protein responsible for the ubiquitination of the APOBEC3 antiviral proteins. Vif folds when it binds the Cullin-RING E3 ligase CRL5 and the transcription cofactor CBF-{beta}. A five-protein complex containing the substrate receptor (Vif, CBF-{beta}, Elongin-B, Elongin-C) and Cullin5 (CUL5) has a published crystal structure, but dynamics of this VCBC-CUL5 complex have not been characterized. Here, we use Molecular Dynamics (MD) simulations and NMR to characterize the dynamics of the VCBC complex with and without CUL5 and APOBEC3 bound. Our simulations show that the VCBC complex undergoes global dynamics involving twisting and clamshell opening of the complex, while VCBC-CUL5 maintains a more static conformation, similar to the crystal structure. This observation from MD is supported by methyl-transverse relaxation optimized spectroscopy (methyl-TROSY) NMR data, which indicates that the entire VCBC complex without CUL5 is dynamic on the s-ms timescale. Vif binds APOBEC3 to recruit it to the complex, and methyl-TROSY NMR shows that the VCBC complex is more conformationally restricted when bound to APOBEC3F, consistent with our MD simulations. Vif contains a flexible linker region located at the hinge of the VCBC complex, which changes conformation in conjuction with the global dynamics of the complex. Like other ubiquitin substrate receptors, VCBC can exist alone or in complex with CUL5 in cells. Accordingly, the VCBC complex could be a good target for therapeutics that would inhibit full assembly of the ubiquitination complex by stabilizing an alternate VCBC conformation.

biophysics↗

bioRxiv2018

Phoneme-level processing in low-frequency cortical responses to speech explained by acoustic features

When we listen to speech, we have to make sense of a waveform of sound pressure. Hierarchical models of speech perception assume that before giving rise to its final semantic meaning, the signal is transformed into unknown intermediate neuronal representations. Classically, studies of such intermediate representations are guided by linguistically defined concepts such as phonemes. Here we argue that in order to arrive at an unbiased understanding of the mechanisms of speech comprehension, the focus should instead lie on representations obtained directly from the stimulus. We illustrate our view with a strongly data-driven analysis of a dataset of 24 young, healthy humans who listened to a narrative of one hour duration while their magnetoencephalogram (MEG) was recorded. We find that two recent results, a performance gain of an encoding model based on acoustic and annotated linguistic features over a model based on acoustic features alone as well as the decoding of subgroups of phonemes from phoneme-locked responses, can be explained with an encoding model entirely based on acoustic features. These acoustic features capitalise on acoustic edges and outperform Gabor-filtered spectrograms, features with the potential to describe the spectrotemporal characteristics of individual phonemes. We conclude that models of brain responses based on linguistic features can serve as excellent benchmarks. However, we put forward that linguistic concepts are better used when interpreting models, not when building them. In doing so, we find that the results of our analyses favour syllables over phonemes as candidate intermediate speech representations visible with fast non-invasive neuroimaging.

neuroscience↗

bioRxiv2018

Increasing Rates of Diagnosis, Substantial Co-occurrence, and Variable Treatment Patterns of Eosinophilic Gastritis, Gastroenteritis and Colitis Based on 10 Year Data Across a Multi-Center Consortium

Financial Support and AcknowledgementsSupport for this project was provided through a research training grant as part of the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) (U54 AI117804). CEGIR is part of the Rare Disease Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS, and is funded through collaboration between NIAID, NIDDK, and NCATS. CEGIR is also supported by patient advocacy groups including APFED CURED and EFC. This project also received support from NIH T32 DK007634 (CCR).\n\nAuthor DisclosersPatricia Fulkerson: Grant funding from the NIH; Consultant for Genentech, Inc; Research support from Knopp Biosciences, LLC.\n\nGary Falk: Research support from Shire, Celgene, Adare, Regeneron. Consulting for Shire\n\nJonathan M. Spergel: Consultant for Regeneron, DBV Technology, Kaleo; Grant funding from DBV Technology, Aimmune Therapeutics, Food Allergy Research Education; Royalties from UpToDate\n\nNirmala Gonsalves: Royalties from UpToDate; Advisory board for Allakos\n\nSandeep K Gupta: Consultant for Alkalos, Abbott, QOL, Receptos; research support from Shire\n\nGlenn Furuta: Founder of EnteroTrack; Consultant for Shire; Royalties from UpToDate\n\nMarc E. Rothenberg: Consultant for Pulm One, Spoon Guru, ClostraBio, Celgene, Shire, Astra Zeneca, GlaxoSmithKline, Allakos, Adare, Regeneron and Novartis and has an equity interest in the first four listed and Immune Pharmaceuticals, and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust) and UpToDate. M.E.R. is an inventor of patents owned by Cincinnati Childrens.\n\nEvan Dellon: Consultant for Adare, Allakos, Alivio, Banner, Celgen/Receptos, Enumeral, GSK, Regeneron, Shire; Research funding from Adare, Celegene/Receptos, Miraca, Meritage, Nutricia, Regeneron, Shire, Educational grant from Banner, Holoclara\n\nStudy HighlightsO_ST_ABSWhat is current knowledge?C_ST_ABSO_LIEosinophilic gastrointestinal disorders (EGIDs) include eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), gastroenteritis (EGE), and colitis (EC).\nC_LIO_LINon-EoE EGIDs are rare with most studies limited to case reports or review of single center experiences.\nC_LIO_LIThere are no widely established guidelines for the diagnosis of EG, EGE, or EC.\nC_LI\n\nWhat is new here?O_LIIn this multicenter study, EG, EGE, and EC were all diagnosed with increasing frequency over the past decade.\nC_LIO_LIPresenting symptoms are non-specific and do not reliably distinguish between disorders.\nC_LIO_LIThere was no male predominance and the majority of subjects had atopy.\nC_LIO_LICo-occurrence of EG, EGE, and EC diagnoses is common, seen in 41% of patients.\nC_LIO_LIThere is substantial variability between centers in initial treatment approaches.\nC_LI

epidemiology↗

bioRxiv2018

Oxytocin promotes synchronized out-group attack during intergroup conflict in humans

Intergroup conflict contributes to human discrimination and violence, but persists because individuals make costly contributions to their groups fighting capacity. Yet how groups effectively synchronize their contributions during intergroup conflict remains poorly understood. Here we examine whether the evolutionary ancient neuropeptide oxytocin provides a neurobiological mechanism underlying group synchronization to attack or defend during real-time intergroup conflict. In a double-blind placebo-controlled study with N=480 males in Attacker-Defender intergroup conflicts, we found that oxytocin reduced attackers contributions and over time increased attackers within-group synchronization of contributions. However, rather than becoming peaceful, oxytocin enabled attackers to track rivals defense-history and synchronize their contributions into well-timed (when defenders were weak) and hence more profitable attacks. Combined, results reveal behavioral synchronization and coordinated action as critical components of successful attacks, subscribe to the possibility that oxytocin enables individuals to contribute to in-group efficiency and prosperity, even when such implies outsiders are excluded or harmed.

neuroscience↗