bluuebunny/crossref_metadata_2025_split huggingface dataset:
Auditory cortical responses to speech are shaped by statistical learning of short-term speech input regularities
Authors: Wu Yunan Charles , Viswanathan Vibha , Abel Taylor J. , Holt Lori L. 
Published: December 2022

AbstractSpeech perception presents an exemplary model of how neurobiological systems flexibly adjust when input departs from the norm. Dialects, accents, and even head colds can negatively impact comprehension by shifting speech from listeners’ expectations. Comprehension improves with exposure to shifted speech regularities, but there is no neurobiological model of this rapid learning. We used electroencephalography to examine human auditory cortical responses to utterances that varied only in fundamental frequency (F0, perceived as voice pitch) as we manipulated the statistical distributions of speech acoustics across listening contexts. Participants overtly categorized speech sampled across two acoustic dimensions that signal /b/ from /p/ (voice onset time [VOT] and F0) to model typical English speech regularities or an expectation-violating accent. These blocks were interleaved with passive exposure to two F0-distinguished test stimuli presented in an oddball ratio to elicit a cortical mismatch negativity (MMN) response. F0 robustly influenced speech categorization when short-term regularities aligned with English but F0 exerted no influence in the context of the accent. The short-term regularities modulated event-related potentials evoked by F0-distinguished test stimuli across both N1 and P3 temporal windows and, for P3 amplitude, there was a strong correlation with perceptual down-weighting of F0. The influence of the short-term regularities persisted to impact MMN in interleaved passive listening blocks when regularities mirrored English but were absent when regularities conveyed the accent. Thus, cortical response is modulated as a function of statistical regularities of the listening context, likely reflecting both early dimension encoding and later categorization.Significance StatementSpeech perception is a quintessential example of how neurobiological systems flexibly adjust when input departs from the norm. Perception is well-tuned to native-language speech patterns. Yet it adjusts when speech diverges from expectations, as with a foreign accent. We observe that the effectiveness of specific cues in speech, like the pitch of a voice, in signaling phonemes like /b/ versus /p/ is dynamically re-weighted when speech violates native-language expectations. We find that this re-weighting is mirrored in cortical responses that reflect both early acoustic dimension encoding and also in later responses linked to phoneme categorization. The results implicate dynamic adjustments in the mapping of speech to cortical representations, as modulated by statistical regularities experienced across local speech input.
Decoding Neural Patterns for the Processing of Fearful Faces under Different Visual Awareness Conditions: A Multivariate Pattern Analysis
Authors: Qiu Zeguo , Li Xuqian , Pegna Alan J. 
Published: December 2022

AbstractMixed findings have been reported for the nonconscious processing of fearful faces. Here, we used multivariate pattern analysis on electroencephalography data from three backward masking experiments to decode the conscious and nonconscious processing of fearful faces. Three groups of participants were shown pairs of faces that were presented either subliminally (16 ms) or supraliminally (266 ms) and were required to complete tasks where the face stimuli were either task-relevant (Experiment 1) or task-irrelevant (Experiments 2 and 3). We decoded the neural activity to examine the temporal dynamics of visual awareness, and to investigate whether the presence and location of a fearful face were processed when levels of awareness varied. The results reveal that the spatial location of fearful faces can be decoded from neural patterns only when they are consciously seen and relevant to participants’ task. Nevertheless, the processing of the mere presence of fearful faces can occur in the absence of visual awareness, and the related neural patterns can be generalised to the conscious, non-spatial processing of fearful faces. Additionally, the flexibility of spatial attention seems to modulate the processing of fearful faces.
Capturing the biology of disease severity in an organoid model of LIS1-lissencephaly
Authors: Zillich Lea , Gasparotto Matteo , Rossetti Andrea Carlo , Fechtner Olivia , Maillard Camille , Hoffrichter Anne , Zillich Eric , Jabali Ammar , Marsoner Fabio , Artioli Annasara , Wilkens Ruven , Schroeter Christina B. , Hentschel Andreas , Witt Stephanie H. , Melzer Nico , Meuth Sven G. , Ruck Tobias , Koch Philipp , Roos Andreas , Bahi-Buisson Nadia , Francis Fiona , Ladewig Julia 
Published: December 2022

AbstractLissencephaly is a malformation of cortical development (MCD) characterized by reduced to absent gyri and a disorganized cortex, leading to severe neurological consequences in affected individuals, including epilepsy, intellectual disability, and reduced life expectancy. Treatments are purely symptomatic, and patients often remain refractory to them. Heterozygous mutations in theLIS1gene, encoding a regulator of the microtubule motor dynein, cause LIS1-lissencephaly. For unknown reasons, LIS1-lissencephaly patients show marked differences in disease severity despite each carrying a heterozygous LIS1 mutation. We leveraged forebrain-type organoids from patients diagnosed with mild, moderate, or severe LIS1-lissencephaly to investigate, in a cytoarchitecture and multi-omics approach, disease and severity grade associated phenotypes, mechanisms, and rescue approaches. We identified alterations of the cytoarchitecture, progenitor cell homeostasis, and neurogenesis often with a severity-dependent gradient. Identified disease-linked molecular mechanisms were microtubule destabilization, WNT-signaling, protein metabolism, and perturbed cadherin- and unfolded protein-binding. Some mechanisms exhibited a severity-dependent gradient or were specific to a severe grade. We present strategies to reverse phenotypic changes in LIS1-patient organoids and identify mTOR pathway inhibitors inin silicodrug repurposing analysis as potential novel therapeutic strategy. By probing the top hit drug, the mTOR inhibitor everolimus, we could indeed rescue severity-dependent phenotypic changes in LIS1-patient organoids. This study demonstrates that organoid-based modeling is sensitive in recapitulating disease severity, which presents an important step in patient stratification, and allows the development of novel personalized rescue strategies with therapeutic potential.
FAP-retargeted Ad5 enablesin vivogene delivery to stromal cells in the tumor microenvironment
Authors: Hartmann K. Patricia , van Gogh Merel , Freitag Patrick C. , Kast Florian , Nagy-Davidescu Gabriela , Borsig Lubor , Plückthun Andreas 
Published: December 2022

AbstractFibroblast activation protein (FAP) is a cell surface serine protease that is highly expressed on reactive stromal fibroblasts, such as cancer-associated fibroblasts (CAFs), and generally absent in healthy adult tissues. FAP expression in the tumor stroma has been detected in more than 90% of all carcinomas, rendering CAFs excellent target cells for a tumor site-specific adenoviral delivery of cancer therapeutics. Here, we present a tropism-modified human adenovirus 5 (Ad5) vector that targets FAP through trivalent, designed ankyrin repeat protein (DARPin)-based retargeting adapters. We describe the development and validation of these adapters via cell-based screening assays and demonstrate adapter-mediated Ad5 retargeting to FAP+fibroblastsin vitroandin vivo. We further show efficientin vivodelivery andin-situproduction of a therapeutic payload by CAFs in the tumor microenvironment (TME), resulting in attenuated tumor growth. We thus propose using our FAP-Ad5 vector to convert CAFs into a ‘biofactory’, secreting encoded cancer therapeutics into the TME to enable a safe and effective cancer treatment.
A duration-dependent interaction between high-intensity light and optical refocus in the drive for myopia control
Authors: Biswas Sayantan , Muralidharan Arumugam R. , Betzler Bjorn Kaijun , Fianza Busoy Joanna Marie , Barathi Veluchamy A. , Tan Royston K. Y. , Shermaine Low Wan Yu , Milea Dan , Kathrani Biten K. , Brennan Noel A. , Najjar Raymond P. 
Published: December 2022

AbstractPURPOSETo evaluate the duration-dependent and synergetic impact of high-intensity light (HL) and optical refocus (RF) on lens-induced myopia (LIM) development in chickens.METHODSMyopia was induced in one eye in chicks (10 groups, n=126) from day 1 post- hatching (D1) until D8 using -10D lenses. Fellow eyes remained uncovered as controls. Nine groups were exposed daily to continuous 2 hours (h), 4h, or 6h of either HL (15,000 lux); RF (removal of -10D lens); or both (HL+RF). One group served as the LIM group without any interventions. Ocular axial length (AL), refractive error, and choroidal thickness were measured on D1, D4, and D8. Outcome measures are expressed as inter-ocular difference (IOD= experimental - control eye) ±SEM.RESULTSBy D8, LIM increased AL (0.36±0.04 mm), myopic refraction (-9.02±0.37D), and choroidal thinning (-90.27±16.44 µm) in the LIM group (all, P<0.001). Compared to the LIM group, exposure to 2h, 4h, or 6h of HL, RF, or HL+RF reduced myopic refraction in a duration-dependent manner, with RF being more effective than HL (P<0.05). Only 6h of HL+RF (not 2h or 4h) prevented LIM and was more effective than RF (P=0.004) or HL (P<0.001) in reducing myopic refraction, and more effective than HL (P<0.001) in reducing axial elongation.CONCLUSIONDaily exposure to 2h, 4h, or 6h of HL, RF, or HL+RF reduced lens-induced myopic refraction in a duration-dependent manner in chickens. Only 6h of HL+RF completely stopped LIM development. The synergetic effect of HL and RF is dependent on the duration of the interventions.
Sensitivity of human sweet taste receptor subunits T1R2 and T1R3 to activation by glucose enantiomers
Authors: Dubovski Nitzan , Galezcki Yaron Ben-Shoshan , Malach Einav , Niv Masha Y. 
Published: December 2022

AbstractWe have previously shown that L-glucose, the non-caloric enantiomer of D-glucose, activates the human sweet taste receptor T1R2/T1R3 transiently expressed in HEK293T cells. Here we show that D- and L-glucose can also activate T1R2 and T1R3 expressed without the counterpart monomer. Serine mutation to alanine in residue 147 in the binding site of T1R3 VFT domain, completely abolishes T1R3S147A activation by either L or D-glucose, while T1R2/T1R3S147A responds in the same way as T1R2 expressed without its counterpart. We further show that the original T1R2 reference sequence (NM_152232.1) is less sensitive by almost an order of magnitude than reference sequence at the time this study was performed (NM_152232.4). We find that out of the four differing positions, it is the R317G in the VFT domain of T1R2, that is responsible for this effect in-vitro. It is important both for practical assay sensitivity, and because glycine is found in this position in ∼20% of the world population. While the effects of the mutations and of the partial transfections were similar for D and L enantiomers, their dose response curves remained distinct, with L-glucose reaching an early plateau.
Multi-modal and multi-model interrogation of large-scale functional brain networks
Authors: Castaldo Francesca , Páscoa dos Santos Francisco , Timms Ryan C , Cabral Joana , Vohryzek Jakub , Deco Gustavo , Woolrich Mark , Friston Karl , Verschure Paul , Litvak Vladimir 
Published: December 2022

AbstractCurrent whole-brain models are generally tailored to the modelling of a particular modality of data (e.g., fMRI or MEG/EEG). Although different imaging modalities reflect different aspects of neural activity, we hypothesise that this activity arises from common network dynamics. Building on the universal principles of self-organising delay-coupled nonlinear systems, we aim to link distinct electromagnetic and metabolic features of brain activity to the dynamics on the brain’s macroscopic structural connectome.To jointly predict dynamical and functional connectivity features of distinct signal modalities, we consider two large-scale models generating local short-lived 40 Hz oscillations with various degrees of realism - namely Stuart Landau (SL) and Wilson and Cowan (WC) models. To this end, we measure features of functional connectivity and metastable oscillatory modes (MOMs) in fMRI and MEG signals - and compare them against simulated data.We show that both models can represent MEG functional connectivity (FC) and functional connectivity dynamics (FCD) to a comparable degree, by varying global coupling and mean conduction time delay. For both models, the omission of delays dramatically decreased the performance. For fMRI, the SL model performed worse for FCD, highlighting the importance of balanced dynamics for the emergence of spatiotemporal patterns of ultra-slow dynamics. Notably, optimal working points varied across modalities and no model was able to achieve a correlation with empirical FC higher than 0.45 across modalities for the same set of parameters. Nonetheless, both displayed the emergence of FC patterns beyond the anatomical framework. Finally, we show that both models can generate MOMs with empirical-like properties.Our results demonstrate the emergence of static and dynamic properties of neural activity at different timescales from networks of delay-coupled oscillators at 40 Hz. Given the higher dependence of simulated FC on the underlying structural connectivity, we suggest that mesoscale heterogeneities in neural circuitry may be critical for the emergence of parallel cross-modal functional networks and should be accounted for in future modelling endeavours.
Differential occupancy and regulatory interactions of KDM6A in bladder cell lines
Authors: Özden-Yılmaz Gülden , Savaş Büşra , Bursalı Ahmet , Eray Aleyna , Arıbaş Alirıza , Şentürk Şerif , Karaca Ezgi , Karakülah Gökhan , Erkek-Ozhan Serap 
Published: December 2022

AbstractEpigenetic deregulation is a critical theme which needs further investigation for bladder cancer research. One of the highly mutated genes in bladder cancer isKDM6A, functioning as a H3K27 demethylase and is part of the MLL3/4 complexes. To decipher the role of KDM6A in normal versus tumor setting, we identified the genomic landscape of KDM6A in normal, immortalized and cancer bladder cells. Our results showed differential KDM6A occupancy at the genes involved in cell differentiation, chromatin organization and Notch signaling depending on the cell type and the mutation status ofKDM6A. Transcription factor motif analysis revealed HES1 to be enriched at KDM6A peaks identified for T24 bladder cancer cell line, which has a truncating mutation in KDM6A, lacking demethylase domain. Our co-immunoprecipitation experiments reveal TLE co-repressors and HES1 as potential truncated and wild type KDM6A interactors. With the aid of structural modeling, we explored how the truncated KDM6A could interact with TLE, HES1, as well RUNX, HHEX transcription factors. These structures provide a solid mean to study the functions of KDM6A independent of its demethylase activity. Collectively, our work provides important contributions to the understanding of KDM6A malfunction in bladder cancer.
Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis
Authors: Potts Margaret A , Mizutani Shinsuke , Garnham Alexandra L , Li Wai Suen Connie S N , Kueh Andrew J , Tai Lin , Pal Martin , Strasser Andreas , Herold Marco J 
Published: December 2022

AbstractMany lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered, DNA sequence data suggest that many more do exist. However, their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cellsin vivo(Mizutani et al, 2022). CRISPR deletion of TFAP4 inEμ-MYCtransgenic hematopoietic stem and progenitor cells (HSPCs) significantly accelerated c-MYC-driven lymphoma development in mice. TFAP4 deficientEμ-MYClymphomas all arose at the pre-B cell stage. Characterization of the transcriptional profile of pre-leukemic pre-B cells inEμ-MYC/Cas9/sgTFAP4transplanted mice, revealed that TFAP4 deletion reduced expression of several master regulators of B cell differentiation, such asSpi1, SpiBandPax5, which all have been shown to be bound by TFAP4. We therefore conclude that loss of TFAP4 leads to a block in differentiation during early B cell development, causing accelerated c-MYC-driven lymphoma development.
Differential response of patient-derived primary glioblastoma cells to metabolic and adhesion inhibitors
Authors: Rezk Rasha , Basar Fikret , Mediavillo John , Donaldson Rebecca , Watts Colin , Franze Kristian , Kabla Alexandre J 
Published: December 2022

PurposeThis study aims to investigate Glioblastoma (GBM) cellular response to adhesion and metabolic inhibitors in the context of cells’ migration and cell-matrix adhesion properties. GBM is the most common incurable brain tumour. Decades of work into GBM chemical and molecular classification have identified mechanisms of drug resistance. Inhibitors targeting cancer cell migration and proliferation rarely take into consideration the heterogeneous migration property amongst cells, which may impact patients’ response to treatment.MethodsTissue samples were obtained from spatially distinct locations with different 5-aminolevulinic acid (5-ALA) fluorescent intensities, strong strongly fluorescent tumour cores, a weak fluorescent tumour rim, and nonfluorescent tumour margins. Samples were previously shown to be associated with different motility and adhesion properties. We tested tumour cells’ response to adhesion and metabolic inhibitors using metabolic assays. Cell survival was also monitored using time-lapse microscopy, while cultured on low-modulus polydimethylsiloxane representative of the stiffness of brain tissue.ResultsMetabolic viability assays, MTT and Cell Titer, showed substantial heterogeneity in drug potency. Highly fluorescent tumour core cells were significantly more resistant to an F0F1 ATP synthase inhibitor (Gboxin), and a FAK inhibitor (GSK2256098), and cell proliferation ceased post-treatment in vitro. Cells derived from non-fluorescent tumour margins exhibited higher potency for the ATP synthase inhibitor (Gboxin). However, cell proliferation persisted post-treatment.ConclusionOur study suggests that the adhesive and migration properties of cells account for the sensitivity to therapeutics in different regions of the tumour in individual patients and between patients with GBM.
How Myopia and Glaucoma Influence the Biomechanical Susceptibility of the Optic Nerve Head
Authors: Chuangsuwanich Thanadet , Tun Tin A. , Braeu Fabian A. , Yeoh Clarice H.Y. , Chong Rachel S. , Wang Xiaofei , Aung Tin , Hoang Quan V. , Girard Michaël J.A. 
Published: December 2022

AbstractPurposeWe aimed to assess optic nerve head (ONH) deformations following acute intraocular pressure (IOP) elevations and horizontal eye movements (adduction and abduction) in control eyes, highly myopic (HM) eyes, HM eyes with glaucoma (HMG), and eyes with pathologic myopia alone (PM) or PM with staphyloma (PM+S).MethodsWe studied 282 eyes, comprising of 99 controls, 51 HM, 35 HMG, 21 PM and 75 PM+S eyes. For each eye, we imaged the ONH using spectral-domain optical coherence tomography (OCT) under the following conditions:(1)primary gaze,(2)20° adduction,(3)20° abduction and(4)primary gaze with acute IOP elevation (to ~35 mmHg) achieved through ophthalmodynamometry. For each OCT volume, we automatically segmented the ONH tissues using deep learning. We performed digital volume correlation (DVC) analysis to compute IOP- and gaze-induced ONH displacements and effective strains (i.e. local deformations). All biomechanical quantities were compared across groups.ResultsUnder IOP elevation, we found that HM eyes exhibited significantly lower strains (3.9 ± 2.4 %) than PM eyes (6.9 ± 5.0%, p < 0.001), HMG eyes (4.7 ± 1.8%, p = 0.04) and PM+S eyes (7.0 ± 5.2%, p < 0.001). Under adduction, we found that HM eyes exhibited significantly lower strains (4.8% ± 2.7%) than PM+S eyes (6.0 ± 3.1%, p = 0.02). We also found significant associations between axial length (or refractive error) and strains - eyes with higher axial length and greater myopia were associated with higher strains. IOP-induced strains were also positively correlated with adduction-induced strains.ConclusionWe found that HMG eyes experienced significantly higher strains under IOP elevations as compared to HM eyes. Additionally, PM+S eyes experienced highest ONH strains as compared to other groups under all biomechanical loads. Our preliminary findings suggest the possibility of using a simple biomechanical test to tease out the susceptibility of HM eyes to further develop glaucoma and/or staphyloma.
Ghost admixture in eastern gorillas
Authors: Pawar Harvinder , Rymbekova Aigerim , Cuadros Sebastian , Huang Xin , de Manuel Marc , van der Valk Tom , Lobon Irene , Alvarez-Estape Marina , Haber Marc , Dolgova Olga , Han Sojung , Esteller-Cucala Paula , Juan David , Ayub Qasim , Bautista Ruben , Kelley Joanna L. , Cornejo Omar E. , Lao Oscar , Andrés Aida M. , Guschanski Katerina , Ssebide Benard , Cranfield Mike , Tyler-Smith Chris , Xue Yali , Prado-Martinez Javier , Marques-Bonet Tomas , Kuhlwilm Martin 
Published: December 2022

AbstractArchaic admixture has had a significant impact on human evolution with multiple events across different clades, including from extinct hominins such as Neanderthals and Denisovans into modern humans. Within the great apes archaic admixture has been identified in chimpanzees and bonobos, but the possibility of such events has not been explored in other species. Here, we address this question using high-coverage whole genome sequences from all four extant gorilla subspecies, including six newly sequenced eastern gorillas from previously unsampled geographic regions. Using Approximate Bayesian Computation (ABC) with neural networks to model the demographic history of gorillas, we find a signature of admixture from an archaic ‘ghost’ lineage into the common ancestor of eastern gorillas, but not western gorillas. We infer that up to 3% of the genome of these individuals is introgressed from an archaic lineage that diverged more than 3 million years ago from the common ancestor of all extant gorillas. This introgression event took place before the split of mountain and eastern lowland gorillas, likely more than 40 thousand years ago, and may have influenced perception of bitter taste in eastern gorillas. When comparing the introgression landscapes of gorillas, humans and bonobos, we find a consistent depletion of introgressed fragments on the X chromosome across these species. However, depletion in protein-coding content is not detectable in eastern gorillas, possibly as a consequence of stronger genetic drift in this species.