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Recognizing sounds implicates the cerebral transformation of input waveforms into semantic representations. Although past research identified the superior temporal gyrus (STG) as a crucial cortical region, the computational fingerprint of these cerebral transformations remains poorly characterized. Here, we exploit a model comparison framework and contrasted the ability of acoustic, semantic (continuous and categorical) and sound-to-event deep neural network representation models to predict perceived sound dissimilarity and 7 T human auditory cortex functional magnetic resonance imaging responses. We confirm that spectrotemporal modulations predict early auditory cortex (Heschl’s gyrus) responses, and that auditory dimensions (for example, loudness, periodicity) predict STG responses and perceived dissimilarity. Sound-to-event deep neural networks predict Heschl’s gyrus responses similar to acoustic models but, notably, they outperform all competing models at predicting both STG responses and perceived dissimilarity. Our findings indicate that STG entails intermediate acoustic-to-semantic sound representations that neither acoustic nor semantic models can account for. These representations are compositional in nature and relevant to behavior.

We tend to mentally segment a series of events according to perceptual contextual changes, such that items from a shared context are more strongly associated in memory than items from different contexts. It is also known that timing context provides a scaffold to structure experiences in memory, but its role in event segmentation has not been investigated. We adapted a previous paradigm, which was used to investigate event segmentation using visual contexts, to study the effects of changes in timing contexts on event segmentation in associative memory. In two experiments, we presented lists of 36 items in which the interstimulus intervals (ISIs) changed after a series of six items ranging between 0.5 and 4 s in 0.5 s steps. After each list, participants judged which one of two test items were shown first (temporal order judgment) for items that were either drawn from the same context (within an ISI) or from consecutive contexts (across ISIs). Further, participants judged from memory whether the ISI associated to an item lasted longer than a standard interval (2.25 s) that was not previously shown (temporal source memory). Experiment 2 further included a time-item encoding task. Results revealed an effect of timing context changes in temporal order judgments, with faster responses (Experiment 1) or higher accuracy (Experiment 2) when items were drawn from the same context, as opposed to items drawn from across contexts. Further, in both experiments, we found that participants were well able to provide temporal source memory judgments based on recalled durations. Finally, replicated across experiments, we found subjective duration bias, as estimated by psychometric curve fitting parameters of the recalled durations, correlated negatively with within-context temporal order judgments. These findings show that changes in timing context support event segmentation in associative memory.

Although lipids are crucial molecules for cell structure, metabolism, and signaling in most organs, they have additional specific functions in the skin. Lipids are required for the maintenance and regulation of the epidermal barrier, physical properties of the skin, and defense against microbes. Analysis of the lipidomeethe totality of lipidseis of similar complexity to those of proteomics or other omics, with lipid structures ranging from simple, linear, to highly complex structures. In addition, the ordering and chemical modifications of lipids have consequences on their biological function, especially in the skin. Recent advances in analytic capability (usually with mass spectrometry), bioinformatic processing, and integration with other dermatological big data have allowed researchers to increasingly understand the roles of specific lipid species in skin biology. In this paper, we review the techniques used to analyze skin lipidomics and epilipidomics.

In a Dutch non-consanguineous patient having mitochondrial encephalomyopathy with complex I and complex IV deficiency, whole exome sequencing revealed two compound heterozygous variants in SLIRP. SLIRP gene encodes a stem-loop RNA-binding protein that regulates mitochondrial RNA expression and oxidative phosphorylation (OXPHOS). A frameshift and a deep-intronic splicing variant reduced the amount of functional wild-type SLIRP RNA to 5%. Consequently, in patient fibroblasts, MT-ND1, MT-ND6, and MT-CO1 expression was reduced. Lentiviral transduction of wild-type SLIRP cDNA in patient fibroblasts increased MT-ND1, MT-ND6, and MT-CO1 expression (2.5–7.2-fold), whereas mutant cDNAs did not. A fourfold decrease of citrate synthase versus total protein ratio in patient fibroblasts indicated that the resulting reduced mitochondrial mass caused the OXPHOS deficiency. Transduction with wild-type SLIRP cDNA led to a 2.4-fold increase of this ratio and partly restored OXPHOS activity. This confirmed causality of the SLIRP variants. In conclusion, we report SLIRP variants as a novel cause of mitochondrial encephalomyopathy with OXPHOS deficiency.

Whole exome sequencing (WES), analyzed with GENESIS and WeGET, revealed a homozygous deletion in the C1QBP gene in a patient with progressive external ophthalmoplegia (PEO) and multiple mtDNA deletions. The gene encodes the mitochondria-located complementary 1 Q subcomponent-binding protein, involved in mitochondrial homeostasis. Biallelic mutations in C1QBP cause mitochondrial cardiomyopathy and/or PEO with variable age of onset. Our patient showed only late-onset PEO-plus syndrome without overt cardiac involvement. Available data suggest that early-onset cardiomyopathy variants localize in important structural domains and PEO-plus variants in the coiled-coil region. Our patient demonstrates that C1QBP mutations should be considered in individuals with PEO with or without cardiomyopathy. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Selective attention enables the preferential processing of relevant stimulus aspects. Invasive animal studies have shown that attending a sound feature rapidly modifies neuronal tuning throughout the auditory cortex. Human neuroimaging studies have reported enhanced auditory cortical responses with selective attention. To date, it remains unclear how the results obtained with functional magnetic resonance imaging (fMRI) in humans relate to the electrophysiological findings in animal models. Here we aim to narrow the gap between animal and human research by combining a selective attention task similar in design to those used in animal electrophysiology with high spatial resolution ultra-high field fMRI at 7 Tesla. Specifically, human participants perform a detection task, whereas the probability of target occurrence varies with sound frequency. Contrary to previous fMRI studies, we show that selective attention resulted in population receptive field sharpening, and consequently reduced responses, at the attended sound frequencies. The difference between our results to those of previous fMRI studies supports the notion that the influence of selective attention on auditory cortex is diverse and may depend on context, stimulus, and task.

Hepatology communications 5(8), 1400-1411 (2021). doi:10.1002/hep4.1728, Published by Wiley, Hoboken, NJ

5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03092-2.

The variety of available mitochondrial quantification tools makes it difficult to select the most reliable and accurate quantification tool. Here, we performed elaborate analyses on five open source ImageJ tools. Excessive clustering of mitochondrial structures was observed in four tools, caused by the global thresholding applied by these tools. The Mitochondrial Analyzer, which uses adaptive thresholding, outperformed the other examined tools, with accurate structural segregation and identification. Additionally, we showed that the Mitochondrial Analyzer successfully identifies mitochondrial morphology differences. Based on the observed performance, we consider the Mitochondrial Analyzer the best open source tool for mitochondrial network morphology quantification.

A solid-phase extraction procedure was optimized to extract 3-fucosyllactose and other human milk oligosaccharides (HMOs) from human milk samples separately, followed by absolute quantitation using high-performance anion-exchange chromatography-pulsed amperometric detection and porous graphitized carbon-liquid chromatography-mass spectrometry, respectively. The approach developed was applied on a pilot sample set of 20 human milk samples and paired infant feces collected at around 1 month postpartum. One-dimensional 1H nuclear magnetic resonance spectroscopy was employed on the same samples to determine the relative levels of fucosylated epitopes and sialylated (Neu5Ac) structural elements. Based on different HMO consumption patterns in the gastrointestinal tract, the infants were assigned to three clusters as follows: complete consumption; specific consumption of non-fucosylated HMOs; and, considerable levels of HMOs still present with consumption showing no specific preference. The consumption of HMOs by infant microbiota also showed structure specificity, with HMO core structures and Neu5Ac(α2-3)-decorated HMOs being most prone to degradation. The degree and position of fucosylation impacted HMO metabolization differently.

Various studies claim that early-learned, culture-typical (canonical) finger configurations used to communicate or represent numerosity, have stronger connections to numerical concepts stored in long-term memory than cultural-unfamiliar finger configurations, thereby allowing for faster access to their numerical meaning. The current study investigated whether presentation of canonical finger configurations gesturing numerosities 1-4 or 6-9 would facilitate young adults' behavioral and neural processing of Arabic numerals. Thirty-one adults performed a number comparison task in which they had to decide whether simultaneously presented Arabic numerals and canonical or non-canonical finger configurations showed the same or a different numerosity, while measuring their performance and Event-Related Potentials (ERPs). The results showed faster responses when comparisons involved canonical (versus non-canonical) finger configurations, but only on numerosity-congruent trials where finger configuration and Arabic numeral matched in number identity. Canonical, and small-number finger configurations 1-4 in general (irrespective of their canonicity), also elicited enhanced amplitude of the early right-parietal P2p, and the later centro-parietal P3 on numerosity-congruent trials. We suggest these P2p and P3 findings respectively reflect facilitated numerical access and easier categorization of canonical finger-numeral configurations. The current results provide behavioral and neurophysiological evidence for the embodiment of culture-specific, canonical, finger-numeral configurations, and their link with other number representations in the adult brain, likely emerging from their more frequent use in daily life communication and/or in early childhood during number symbol acquisition.

Tinnitus is a clinical condition where a sound is perceived without an external sound source. Homeostatic plasticity (HSP), serving to increase neural activity as compensation for the reduced input to the auditory pathway after hearing loss, has been proposed as a mechanism underlying tinnitus. In support, animal models of tinnitus show evidence of increased neural activity after hearing loss, including increased spontaneous and sound-driven firing rate, as well as increased neural noise throughout the auditory processing pathway. Bridging these findings to human tinnitus, however, has proven to be challenging. Here we implement hearing loss-induced HSP in a Wilson-Cowan Cortical Model of the auditory cortex to predict how homeostatic principles operating at the microscale translate to the meso- to macroscale accessible through human neuroimaging. We observed HSP-induced response changes in the model that were previously proposed as neural signatures of tinnitus, but that have also been reported as correlates of hearing loss and hyperacusis. As expected, HSP increased spontaneous and sound-driven responsiveness in hearing-loss affected frequency channels of the model. We furthermore observed evidence of increased neural noise and the appearance of spatiotemporal modulations in neural activity, which we discuss in light of recent human neuroimaging findings. Our computational model makes quantitative predictions that require experimental validation, and may thereby serve as the basis of future human studies of hearing loss, tinnitus, and hyperacusis.

Aims The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups. Methods and results We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping. Conclusion The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach., Graphical Abstract

BackgroundPandemics, even more than other medical problems, require swift integration of knowledge. When caused by a new virus, understanding the underlying biology may help finding solutions. In a setting where there are a large number of loosely related projects and initiatives, we need common ground, also known as a “commons.” Wikidata, a public knowledge graph aligned with Wikipedia, is such a commons and uses unique identifiers to link knowledge in other knowledge bases. However, Wikidata may not always have the right schema for the urgent questions. In this paper, we address this problem by showing how a data schema required for the integration can be modeled with entity schemas represented by Shape Expressions.ResultsAs a telling example, we describe the process of aligning resources on the genomes and proteomes of the SARS-CoV-2 virus and related viruses as well as how Shape Expressions can be defined for Wikidata to model the knowledge, helping others studying the SARS-CoV-2 pandemic. How this model can be used to make data between various resources interoperable is demonstrated by integrating data from NCBI (National Center for Biotechnology Information) Taxonomy, NCBI Genes, UniProt, and WikiPathways. Based on that model, a set of automated applications or bots were written for regular updates of these sources in Wikidata and added to a platform for automatically running these updates.ConclusionsAlthough this workflow is developed and applied in the context of the COVID-19 pandemic, to demonstrate its broader applicability it was also applied to other human coronaviruses (MERS, SARS, human coronavirus NL63, human coronavirus 229E, human coronavirus HKU1, human coronavirus OC4).

PURPOSE: The trabecular meshwork (TM) is situated in the most frontal part of the eye and is thought to play an important role in the regulation of the eye pressure. However, this tissue is rather difficult to harvest for research. The purpose of this study is therefore to integrate the existing gene expression data of the healthy TM to increase sample size and identify its signature genes and pathways. This provides a robust reference for the study of molecular disease processes and supports the selection of candidate target genes for new treatments.METHODS: A systematic search identified microarray data of healthy TM tissue. After quality control, datasets of low quality and deviating samples were excluded. Remaining individuals were jointly normalized and integrated into one database. The average gene expression of each tested gene over all individuals was calculated. The 25% genes with the highest average expression were identified as the most active genes in the healthy TM and used as input for pathway and network analysis. Additionally, ubiquitous pathways and genes were identified and excluded from the results. Lastly, we identified genes which are likely to be TM-specific.RESULTS: The gene expression data of 44 individuals, obtained from 18 datasets, were jointly normalized. Ubiquitous genes (n = 688) and ubiquitous pathways (n = 73) were identified and excluded. Following, 1882 genes and 211 pathways were identified as the signature genes and pathways of the healthy TM. Pathway analysis revealed multiple molecular processes of which some were already known to be active in the TM, for example extracellular matrix and elastic fiber formation. Forty-six candidate TM-specific genes were identified. These consist mainly of pseudogenes or novel transcripts of which the function is unknown.CONCLUSIONS: In this comprehensive meta-analysis we identified non-ubiquitous genes and pathways that form the signature of the functioning of the healthy TM. Additionally, 46 candidate TM-specific genes were identified. This method can also be used for other tissues that are difficult to obtain for study.

Contains fulltext : 220697.pdf (Publisher’s version ) (Open Access) When speech perception is difficult, one way listeners adjust is by reconfiguring phoneme category boundaries, drawing on contextual information. Both lexical knowledge and lipreading cues are used in this way, but it remains unknown whether these two differing forms of perceptual learning are similar at a neural level. This study compared phoneme boundary adjustments driven by lexical or audiovisual cues, using ultra-high-field 7-T fMRI. During imaging, participants heard exposure stimuli and test stimuli. Exposure stimuli for lexical retuning were audio recordings of words, and those for audiovisual recalibration were audio-video recordings of lip movements during utterances of pseudowords. Test stimuli were ambiguous phonetic strings presented without context, and listeners reported what phoneme they heard. Reports reflected phoneme biases in preceding exposure blocks (e.g., more reported /p/ after /p/-biased exposure). Analysis of corresponding brain responses indicated that both forms of cue use were associated with a network of activity across the temporal cortex, plus parietal, insula, and motor areas. Audiovisual recalibration also elicited significant occipital cortex activity despite the lack of visual stimuli. Activity levels in several ROIs also covaried with strength of audiovisual recalibration, with greater activity accompanying larger recalibration shifts. Similar activation patterns appeared for lexical retuning, but here, no significant ROIs were identified. Audiovisual and lexical forms of perceptual learning thus induce largely similar brain response patterns. However, audiovisual recalibration involves additional visual cortex contributions, suggesting that previously acquired visual information (on lip movements) is retrieved and deployed to disambiguate auditory perception. 14 p.

There is an increasing interest in microRNAs (miRNAs) as they are of utmost importance in gene regulation at the posttranscriptional level. Sex-related susceptibility for non-communicable diseases later in life could originate in early life. Until now, no data on sex-specific miRNA expression are available for the placenta. Therefore, we investigated the difference by sex of newborn's miRNA expression in human placental tissue. Within the ENVIRONAGE birth cohort, miRNA and mRNA expression profiling was performed in 60 placentae (50% boys) using Agilent (8 x 60 K) microarrays. The distribution of chromosome locations was studied and pathway analysis of the identified sex-specific miRNAs in the placenta was carried out. Of the total 2558 miRNAs on the array, 597 miRNAs were expressed in over 70% of the samples and were included for further analyses. A total of 142 miRNAs were significantly (FDR

The hippocampus and dorsal striatum are both associated with temporal processing, but they are thought to play distinct roles. The hippocampus has been reported to contribute to storing temporal structure of events in memory, whereas the striatum contributes to temporal motor preparation and reward anticipation. Here, we asked whether the striatum cooperates with the hippocampus in processing the temporal context of memorized visual associations. In our task, participants were trained to implicitly form temporal expectations for one of two possible time intervals associated to specific cue-target associations, and subsequently were scanned using 7T functional magnetic resonance imaging. During scanning, learned temporal expectations could be violated when the pairs were presented at either the learned or not-learned time intervals. When temporal expectations were not met during testing trials, activity in hippocampal subfields CA3/CA2 and CA1 decreased while right putamen activity increased, compared to when temporal expectations were met. Further, psycho-physiological interactions showed that functional connectivity between left CA1 and caudate, as well as between putamen and caudate, decreased when temporal expectations were not met. Our results indicate that the hippocampus and striatum cooperate to process implicit temporal expectation from mnemonic associations, with different but complementary contributions from caudate and putamen. Our findings provide further support for a hippocampal-striatal network in temporal associative processing.

Background: Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. Methods: This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m 2) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m 2; 40–65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. Results: Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. Conclusions: In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.

Contains fulltext : 219584.pdf (Publisher’s version ) (Closed access) To adapt to situations in which speech perception is difficult, listeners can adjust boundaries between phoneme categories using perceptual learning. Such adjustments can draw on lexical information in surrounding speech, or on visual cues via speech-reading. In the present study, listeners proved they were able to flexibly adjust the boundary between two plosive/stop consonants, /p/-/t/, using both lexical and speech-reading information and given the same experimental design for both cue types. Videos of a speaker pronouncing pseudo-words and audio recordings of Dutch words were presented in alternating blocks of either stimulus type. Listeners were able to switch between cues to adjust phoneme boundaries, and resulting effects were comparable to results from listeners receiving only a single source of information. Overall, audiovisual cues (i.e., the videos) produced the stronger effects, commensurate with their applicability for adapting to noisy environments. Lexical cues were able to induce effects with fewer exposure stimuli and a changing phoneme bias, in a design unlike most prior studies of lexical retuning. While lexical retuning effects were relatively weaker compared to audiovisual recalibration, this discrepancy could reflect how lexical retuning may be more suitable for adapting to speakers than to environments. Nonetheless, the presence of the lexical retuning effects suggests that it may be invoked at a faster rate than previously seen. In general, this technique has further illuminated the robustness of adaptability in speech perception, and offers the potential to enable further comparisons across differing forms of perceptual learning. 9 p.

Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC. In the developing mPFC, we observed decreased myelin-related gene expression that persisted into adulthood. Environmental enrichment applied during adolescence restored parvalbumin interneuron hypomyelination as well as cognitive inflexibility. Collectively, these findings highlight that impairment of parvalbumin interneuron myelination is related to schizophrenia-relevant cognitive deficits., Dysfunction of GABAergic neurons in the prefrontal cortex has been reported in schizophrenia. Here, the authors use the apomorphine-susceptible rat, which displays some schizophrenia-like behaviors, and show that interneurons in the medial prefrontal cortex are hypomyelinated, which may contribute to this behavioral phenotype.

Purpose Performing bioinformatics analyses using trabecular meshwork (TM) gene expression data in order to further elucidate the molecular pathogenesis of primary open-angle glaucoma (POAG), and to identify candidate target genes. Methods A systematic search in Gene Expression Omnibus and ArrayExpress was conducted, and quality control and preprocessing of the data was performed with ArrayAnalysis.org. Molecular pathway overrepresentation analysis was performed with PathVisio using pathway content from three pathway databases: WikiPathways, KEGG and Reactome. In addition, Gene Ontology (GO) analysis was performed on the gene expression data. The significantly changed pathways were clustered into functional categories which were combined into a network of connected genes. Results Ninety-two significantly changed pathways were clustered into five functional categories: extracellular matrix (ECM), inflammation, complement activation, senescence and Rho GTPase signalling. ECM included pathways involved in collagen, actin and cell-matrix interactions. Inflammation included pathways entailing NF-kappa B and arachidonic acid. The network analysis showed that several genes overlap between the inflammation cluster on the one hand, and the ECM, complement activation and senescence clusters on the other hand. GO analysis, identified additional clusters, related to development and corticosteroids. Conclusion This study provides an overview of the processes involved in the molecular pathogenesis of POAG in the TM. The results show good face validity and confirm findings from histological, biochemical, genome-wide association and transcriptomics studies. The identification of known points of action for drugs, such as Rho GTPase, arachidonic acid, NF-kappa B, prostaglandins and corticosteroid clusters, supports the value of this approach to identify potential drug targets.

Contains fulltext : 219192.pdf (Publisher’s version ) (Closed access) Auditory spatial tasks induce functional activation in the occipital - visual - cortex of early blind humans. Less is known about the effects of blindness on auditory spatial processing in the temporal - auditory - cortex. Here, we investigated spatial (azimuth) processing in congenitally and early blind humans with a phase-encoding functional magnetic resonance imaging (fMRI) paradigm. Our results show that functional activation in response to sounds in general- independent of sound location - was stronger in the occipital cortex but reduced in the medial temporal cortex of blind participants in comparison with sighted participants. Additionally, activation patterns for binaural spatial processing were different for sighted and blind participants in planum temporale. Finally, fMRI responses in the auditory cortex of blind individuals carried less information on sound azimuth position than those in sighted individuals, as assessed with a 2-channel, opponent coding model for the cortical representation of sound azimuth. These results indicate that early visual deprivation results in reorganization of binaural spatial processing in the auditory cortex and that blind individuals may rely on alternative mechanisms for processing azimuth position. 14 p.

Gefitinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits the epidermal growth factor receptor (EGFR), hampering cell growth and proliferation. Due to its action, gefitinib has been used in the treatment of cancers that present abnormally increased expression of EGFR. However, side effects from gefitinib therapy may occur, among which diarrhoea is most common, that can lead to interruption of the planned therapy in the more severe cases. The mechanisms underlying intestinal toxicity induced by gefitinib are not well understood. Therefore, this study aims at providing insight into these mechanisms based on transcriptomic responses induced in vitro. A 3D culture of healthy human colon and small intestine (SI) organoids was exposed to 0.1, 1, 10 and 30 µM of gefitinib, for a maximum of three days. These drug concentrations were selected using physiologically-based pharmacokinetic simulation considering patient dosing regimens. Samples were used for the analysis of viability and caspase 3/7 activation, image-based analysis of structural changes, as well as RNA isolation and sequencing via high-throughput techniques. Differential gene expression analysis showed that gefitinib perturbed signal transduction pathways, apoptosis, cell cycle, FOXO-mediated transcription, p53 signalling pathway, and metabolic pathways. Remarkably, opposite expression patterns of genes associated with metabolism of lipids and cholesterol biosynthesis were observed in colon versus SI organoids in response to gefitinib. These differences in the organoids’ responses could be linked to increased activated protein kinase (AMPK) activity in colon, which can influence the sensitivity of the colon to the drug. Therefore, this study sheds light on how gefitinib induces toxicity in intestinal organoids and provides an avenue towards the development of a potential tool for drug screening and development.

Listeners can rely on perceptual learning and recalibration in order to make reliable interpretations during speech perception. Lexical and audiovisual (or speech-read) information can disambiguate the incoming auditory signal when it is unclear, due to speaker-related characteristics, such as an unfamiliar accent, or due to environmental factors, such as noise. With experience, listeners can learn to adjust boundaries between phoneme categories as a means of adaptation to such inconsistencies. Recalibration experiments tend to use a targeted approach by embedding ambiguous phonemes into speech or speechlike items, and with continuous exposure, a learning effect can be induced in listeners, wherein disambiguating contextual information shifts the perceived identity of the same ambiguous sound. The following chapter will review current and past literature regarding lexical and audiovisual influences on phoneme boundary recalibration, as well as theories and neuroimaging data that potentially reveal what facilitates this perceptual plasticity.keywordsrecalibrationperceptual learningspeech perceptionphonetic processinglexical processingaudiovisual speechspeech-reading.

Neural oscillations and their synchronization play an important role in functions such as perception and learning. In this thesis, a phase oscillator model is used to simulate the dynamics of neural networks of the brain, where each group of neurons is considered as a phase oscillator. The process of learning has been investigated in the form of synaptic and myelin plasticity in an abstract network which can represent neural networks at any spatial scale. The role of gamma oscillations and their synchronization is identified in the perception and perceptual learning of figure-ground segregation. Here, texture stimuli are used in psychophysics experimentation as well as in computational models that simulate synchronization of gamma oscillations and plasticity in the primary visual cortex (V1).

SummaryThroughout the chapters in this book, pathways are used to visualize how genetically inheritable metabolic disorders are related. These pathways provide common conceptual models which explain groups of chemical reactions within their biological context. Visual representations of the reactions in biological pathway diagrams provide intuitive ways to study the complex metabolic processes. In order to link (clinical) data to these pathways, they have to be understood by computers. Understanding how to move from a regular pathway drawing to its machine-readable counterpart is pertinent for creating proper models. This chapter outlines the various aspects of the digital counterparts of the pathway diagrams in this book, connecting them to databases and using them in data integration and analysis. This is followed by three examples of bioinformatics applications including a pathway enrichment analysis, a biological network extension, and a final example that integrates pathways with clinical biomarker data.

Scope: Persistent DNA methylation changes may mediate the effects of early-life exposures on later-life health. However, because the length of the human lifespan is challenging for prospective studies, there are few relevant data from human longitudinal studies. Projecting data from mouse models of early-life exposure to existing human studies offers a potential tool to address this research challenge. Methods and Results: C57BL/6J mice were fed low or normal folate diets before and during pregnancy and lactation. Genome-wide promoter methylation was measured in male offspring livers at 17.5 days gestation and 28 weeks. Eight gene promoters were concurrently hypermethylated by folate depletion in fetuses and adults (>1.10 fold-change; pConclusion: Some persistent folate-induced methylation changes observed in mice were mirrored in humans. This demonstrates utility of mouse data in identifying human loci for interrogation as biomarkers of later-life health.

In everyday life, the processing of acoustic information allows us to react to subtle changes in the auditory scene. Yet even when closely attending to sounds in the context of a task, we occasionally miss task-relevant features. The neural computations that underlie our ability to detect behavioral relevant sound changes are thought to be grounded in both feedforward and feedback processes within the auditory hierarchy. Here, we assessed the role of feedforward and feedback contributions in primary and non-primary auditory areas during behavioral detection of target sounds using submillimeter spatial resolution functional magnetic resonance imaging (fMRI) at high-fields (7 T) in humans. We demonstrate that the successful detection of subtle temporal shifts in target sounds leads to a selective increase of activation in superficial layers of primary auditory cortex (PAC). These results indicate that feedback signals reaching as far back as PAC may be relevant to the detection of targets in the auditory scene.

Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (n = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (n = 325) and the Maastricht Study (n = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.

We study the synchronization of small-world networks of identical coupled phase oscillators through the Kuramoto interaction and uniform time delay. For a given intrinsic frequency and coupling constant, we observe synchronization enhancement in a range of time delays and discontinuous transition from the partially synchronized state with defect patterns to a glassy phase, characterized by a distribution of randomly frozen phase-locked oscillators. By further increasing the time delay, this phase undergoes a discontinuous transition to another partially synchronized state. We found the bimodal frequency distributions and hysteresis loops as indicators of the discontinuous nature of these transitions. Moreover, we found the existence of Chimera states at the onset of transitions.

Recent functional MRI (fMRI) studies have highlighted differences in responses to natural sounds along the rostral-caudal axis of the human superior temporal gyrus. However, due to the indirect nature of the fMRI signal, it has been challenging to relate these fMRI observations to actual neuronal response properties. To bridge this gap, we present a forward model of the fMRI responses to natural sounds combining a neuronal model of the auditory cortex with physiological modeling of the hemodynamic BOLD response. Neuronal responses are modeled with a dynamic recurrent firing rate model, reflecting the tonotopic, hierarchical processing in the auditory cortex along with the spectro-temporal tradeoff in the rostral-caudal axis of its belt areas. To link modeled neuronal response properties with human fMRI data in the auditory belt regions, we generated a space of neuronal models, which differed parametrically in spectral and temporal specificity of neuronal responses. Then, we obtained predictions of fMRI responses through a biophysical model of the hemodynamic BOLD response (P-DCM). Using Bayesian model comparison, our results showed that the hemodynamic BOLD responses of the caudal belt regions in the human auditory cortex were best explained by modeling faster temporal dynamics and broader spectral tuning of neuronal populations, while rostral belt regions were best explained through fine spectral tuning combined with slower temporal dynamics. These results support the hypotheses of complementary neural information processing along the rostral-caudal axis of the human superior temporal gyrus.

Mitochondria change their shape, size and number, in response to cellular demand, through mitochondrial dynamics. The interaction between mitochondria and the ER, through ER-mitochondrial contact sites, is crucial in mitochondrial dynamics. Several protein complexes tethering mitochondria to the ER include proteins involved in fission or fusion but also proteins involved in calcium homeostasis, which is known to affect mitochondrial dynamics. The formation of these contact sites are especially important for mitochondrial fission as these contact sites induce both outer and inner membrane constriction, prior to recruitment of Drp1. While the exact molecular mechanisms behind these constrictions remain uncertain, several hypotheses have been proposed. In this review, we discuss the involvement of tethering complexes in mitochondrial dynamics and provide an overview of the current knowledge and hypotheses on the constriction of the outer and inner mitochondrial membrane at ER-mitochondrial contact sites.

Following rapid methodological advances, ultra-high field (UHF) functional and anatomical magnetic resonance imaging (MRI) has been repeatedly and successfully used for the investigation of the human auditory system in recent years. Here, we review this work and argue that UHF MRI is uniquely suited to shed light on how sounds are represented throughout the network of auditory brain regions. That is, the provided gain in spatial resolution at UHF can be used to study the functional role of the small subcortical auditory processing stages and details of cortical processing. Further, by combining high spatial resolution with the versatility of MRI contrasts, UHF MRI has the potential to localize the primary auditory cortex in individual hemispheres. This is a prerequisite to study how sound representation in higher-level auditory cortex evolves from that in early (primary) auditory cortex. Finally, the access to independent signals across auditory cortical depths, as afforded by UHF, may reveal the computations that underlie the emergence of an abstract, categorical sound representation based on low-level acoustic feature processing. Efforts on these research topics are underway. Here we discuss promises as well as challenges that come with studying these research questions using UHF MRI, and provide a future outlook.

Severely motor-disabled patients, such as those suffering from the so-called “locked-in” syndrome, cannot communicate naturally. They may benefit from brain-computer interfaces (BCIs) exploiting brain signals for communication and therewith circumventing the muscular system. One BCI technique that has gained attention recently is functional near-infrared spectroscopy (fNIRS). Typically, fNIRS-based BCIs allow for brain-based communication via voluntarily modulation of brain activity through mental task performance guided by visual or auditory instructions. While the development of fNIRS-BCIs has made great progress, the reliability of fNIRS-BCIs across time and environments has rarely been assessed. In the present fNIRS-BCI study, we tested six healthy participants across three consecutive days using a straightforward four-choice fNIRS-BCI communication paradigm that allows answer encoding based on instructions using various sensory modalities. To encode an answer, participants performed a motor imagery task (mental drawing) in one out of four time periods. Answer encoding was guided by either the visual, auditory, or tactile sensory modality. Two participants were tested outside the laboratory in a cafeteria. Answers were decoded from the time course of the most-informative fNIRS channel-by-chromophore combination. Across the three testing days, we obtained mean single- and multi-trial (joint analysis of four consecutive trials) accuracies of 62.5 and 85.19%, respectively. Obtained multi-trial accuracies were 86.11% for visual, 80.56% for auditory, and 88.89% for tactile sensory encoding. The two participants that used the fNIRS-BCI in a cafeteria obtained the best single- (72.22 and 77.78%) and multi-trial accuracies (100 and 94.44%). Communication was reliable over the three recording sessions with multi-trial accuracies of 86.11% on day 1, 86.11% on day 2, and 83.33% on day 3. To gauge the trade-off between number of optodes and decoding accuracy, averaging across two and three promising fNIRS channels was compared to the one-channel approach. Multi-trial accuracy increased from 85.19% (one-channel approach) to 91.67% (two-/three-channel approach). In sum, the presented fNIRS-BCI yielded robust decoding results using three alternative sensory encoding modalities. Further, fNIRS-BCI communication was stable over the course of three consecutive days, even in a natural (social) environment. Therewith, the developed fNIRS-BCI demonstrated high flexibility, reliability and robustness, crucial requirements for future clinical applicability.

Genome-scale metabolic models (GEMs) are comprehensive knowledge bases of cellular metabolism and serve as mathematical tools for studying biological phenotypes and metabolic states or conditions in various organisms and cell types. Given the sheer size and complexity of human metabolism, selecting parameters for existing analysis methods such as metabolic objective functions and model constraints is not straightforward in human GEMs. In particular, comparing several conditions in large GEMs to identify condition- or disease-specific metabolic features is challenging. In this study, we showcase a scalable, model-driven approach for an in-depth investigation and comparison of metabolic states in large GEMs which enables identifying the underlying functional differences. Using a combination of flux space sampling and network analysis, our approach enables extraction and visualisation of metabolically distinct network modules. Importantly, it does not rely on known or assumed objective functions. We apply this novel approach to extract the biochemical differences in adipocytes arising due to unlimited vs blocked uptake of branched-chain amino acids (BCAAs, considered as biomarkers in obesity) using a human adipocyte GEM (iAdipocytes1809). The biological significance of our approach is corroborated by literature reports confirming our identified metabolic processes (TCA cycle and Fatty acid metabolism) to be functionally related to BCAA metabolism. Additionally, our analysis predicts a specific altered uptake and secretion profile indicating a compensation for the unavailability of BCAAs. Taken together, our approach facilitates determining functional differences between any metabolic conditions of interest by offering a versatile platform for analysing and comparing flux spaces of large metabolic networks., Author summary Cellular metabolism is a highly complex and interconnected system. As many lifestyle diseases in humans have a strong metabolic component, it is important to understand metabolic differences between healthy and diseased states. In systems biology, metabolic behaviours are investigated using genome-scale metabolic models. In addition to the sheer size and complexity of the genome-scale metabolic models of human systems, using existing analysis methods is challenging and the parameter selection is not straightforward. Therefore, novel methodological frameworks are necessary for analysing metabolic conditions despite the challenges posed by human models. Particularly, an ongoing challenge has been that of comparing several phenotypes for identifying condition- or disease-specific metabolic signatures. We address this significant challenge by developing a scalable and model-driven approach, ComMet (Comparison of Metabolic states). ComMet enables an in-depth investigation and comparison of metabolic phenotypes in large models while also identifying the underlying functional differences. Novel hypotheses can be generated using ComMet for not only understanding known metabolic phenotypes better but also for guiding the design of new experiments to validate the processes predicted by ComMet.

Invasive and non-invasive electrophysiological measurements during “cocktail-party”-like listening indicate that neural activity in human auditory cortex (AC) “tracks” the envelope of relevant speech. Due to the measurements’ limited coverage and/or spatial resolution, however, the distinct contribution of primary and non-primary auditory areas remains unclear. Using 7-Tesla fMRI, here we measured brain responses of participants attending to one speaker, without and with another concurrent speaker. Using voxel-wise modeling, we observed significant speech envelope tracking in bilateral Heschl’s gyrus (HG) and middle superior temporal sulcus (mSTS), despite the sluggish fMRI responses and slow temporal sampling. Neural activity was either positively (HG) or negatively (mSTS) correlated to the speech envelope. Spatial pattern analyses indicated that whereas tracking in HG reflected both relevant and (to a lesser extent) non-relevant speech, right mSTS selectively represented the relevant speech signal. These results indicate that primary and non-primary AC antithetically process ongoing speech suggesting a push-pull of acoustic and linguistic information.

SCOPE: It has been proposed that endogenously formed N-nitroso compounds (NOCs) are partly responsible for the link between red meat consumption and colorectal cancer (CRC) risk. As nitrite has been indicated as critical factor in the formation of NOCs, we evaluated the impact of replacing the additive sodium nitrite (E251) by botanical extracts in the PHYTOME project. METHOD AND RESULTS: A human dietary intervention study was conducted in which healthy subjects consumed 300 grams of meat for two weeks, in subsequent order: conventional processed red meat, white meat, and processed red meat with standard or reduced levels of nitrite and added phytochemicals. Consumption of red meat products enriched with phytochemicals leads to a significant reduction in the faecal excretion of NOCs, as compared to traditionally processed red meat products. Gene expression changes identify cell proliferation as main affected molecular mechanism. High nitrate levels in drinking water in combination with processed red meat intake further stimulates NOC formation, an effect that could be mitigated by replacement of E251 by natural plant extracts. CONCLUSION: These findings suggest that addition of natural extracts to conventionally processed red meat products may help to reduce CRC risk, which is mechanistically supported by gene expression analyses.

Transcranial alternating current stimulation (tACS) at 10Hz has been shown to modulate spatial attention. However, the frequency-specificity and the oscillatory changes underlying this tACS effect are still largely unclear. Here, we applied high-definition tACS at individual alpha frequency (IAF), two control frequencies (IAF+/-2Hz) and sham to the left posterior parietal cortex and measured its effects on visuospatial attention performance and offline alpha power (using electroencephalography, EEG). We revealed a behavioural and electrophysiological stimulation effect relative to sham for IAF but not control frequency stimulation conditions: there was a leftward lateralization of alpha power for IAF tACS, which differed from sham for the first out of three minutes following tACS. At a high value of this EEG effect (moderation effect), we observed a leftward attention bias relative to sham. This effect was task-specific, i.e. it could be found in an endogenous attention but not in a detection task. Only in the IAF tACS condition, we also found a correlation between the magnitude of the alpha lateralization and the attentional bias effect. Our results support a functional role of alpha oscillations in visuospatial attention and the potential of tACS to modulate it. The frequency-specificity of the effects suggests that an individualization of the stimulation frequency is necessary in heterogeneous target groups with a large variation in IAF.

BackgroundWhereas several engineered nanomaterials are able to incite toxicological effects, the underlying molecular processes are understudied. And the varied physicochemical properties complicate toxicological predictions. Gene expression data allow us to study the cell-specific responses of individual genes, whereas their role in biological processes is harder to interpret. An overrepresentation analysis allows us to identify enriched biological processes and link the experimental data to these, but still prompt broad results which complicates the analysis of detailed toxicological processes. We demonstrated a targeted filtering approach to compare the cell-specific effects of two concentrations of the widely used nanomaterial titanium dioxide (TiO2) -nanobelts.MethodsWe compared public gene expression data generated by Tilton et al. from colon endothelium cells (Caco2), lung endothelium cells (SAE), and monocytic like cells (THP1) after 24-hour exposure to low (10 μg/ml) and high (100 μg/ml) concentrations of TiO2 -nanobelts. We used pathway enrichment analysis of the WikiPathways collection to identify cell and concentration-specific affected pathways. Gene sets from selected Gene Ontology terms (apoptosis, inflammation, DNA damage response and oxidative stress) highlighted pathways with a clear toxicity focus. Finally, pathway-gene networks were created to show the genetic overlap between the altered toxicity-related pathways.ResultsAll cell lines showed more differentially expressed genes after exposure to higher concentration, but our analysis found clear differences in affected molecular processes between the cell lines. Approximately half of the affected pathways are categorized with one of the selected toxicity-related processes. Caco2 cells show resilience to low and high concentrations. SAE cells display some cytotoxic response to the high concentration, while THP1 cells are already strongly affected at a low concentration. The networks show for up- and downregulation for the THP1 cells the most pathways. Additionally, the networks show gene overlap between almost all pathways for all conditions.ConclusionsThe approach allowed us to focus the analysis on affected cytotoxic processes and highlight cell-specific effects. The results showed that Caco2 cells are more resilient to TiO2 -nanobelts exposure compared to SAE cells, while THP1 cells were affected the most. The automated workflow can be easily adapted using other Gene Ontology terms focusing on other biological processes.

Numerous neuroimaging studies demonstrated that the auditory cortex tracks ongoing speech and that, in multi-speaker environments, tracking of the attended speaker is enhanced compared to the other irrelevant speakers. In contrast to speech, multi-instrument music can be appreciated by attending not only on its individual entities (i.e., segregation) but also on multiple instruments simultaneously (i.e., integration). We investigated the neural correlates of these two modes of music listening using electroencephalography (EEG) and sound envelope tracking. To this end, we presented uniquely composed music pieces played by two instruments, a bassoon and a cello, in combination with a previously validated music auditory scene analysis behavioral paradigm (Disbergen et al., 2018). Similar to results obtained through selective listening tasks for speech, relevant instruments could be reconstructed better than irrelevant ones during the segregation task. A delay-specific analysis showed higher reconstruction for the relevant instrument during a middle-latency window for both the bassoon and cello and during a late window for the bassoon. During the integration task, we did not observe significant attentional modulation when reconstructing the overall music envelope. Subsequent analyses indicated that this null result might be due to the heterogeneous strategies listeners employ during the integration task. Overall, our results suggest that subsequent to a common processing stage, top-down modulations consistently enhance the relevant instrument’s representation during an instrument segregation task, whereas such an enhancement is not observed during an instrument integration task. These findings extend previous results from speech tracking to the tracking of multi-instrument music and, furthermore, inform current theories on polyphonic music perception.

Multi-Voxel Pattern Analysis (MVPA) is a well established tool to disclose weak, distributed effects in brain activity patterns. The generalization ability is assessed by testing the learning model on new, unseen data. However, when limited data is available, the decoding success is estimated using cross-validation. There is general consensus on assessing statistical significance of cross-validated accuracy with non-parametric permutation tests. In this work we focus on the false positive control of different permutation strategies and on the statistical power of different cross-validation schemes. With simulations, we show that estimating the entire cross-validation error on each permuted dataset is the only statistically valid permutation strategy. Furthermore, using both simulations and real data from the HCP WU-Minn 3T fMRI dataset, we show that, among the different cross-validation schemes, a repeated split-half cross-validation is the most powerful, despite achieving slightly lower classification accuracy, when compared to other schemes. Our findings provide additional insights into the optimization of the experimental design for MVPA, highlighting the benefits of having many short runs.

Recent studies have highlighted the possible contributions of direct connectivity between early sensory cortices to audiovisual integration. Anatomical connections between the early auditory and visual cortices are concentrated in visual sites representing the peripheral field of view. Here, we aimed to engage early sensory interactive pathways with simple, far-peripheral audiovisual stimuli (auditory noise and visual gratings). Using a modulation detection task in one modality performed at an 84% correct threshold level, we investigated multisensory interactions by simultaneously presenting weak stimuli from the other modality in which the temporal modulation was barely-detectable (at 55 and 65% correct detection performance). Furthermore, we manipulated the temporal congruence between the cross-sensory streams. We found evidence for an influence of barely-detectable visual stimuli on the response times for auditory stimuli, but not for the reverse effect. These visual-to-auditory influences only occurred for specific phase-differences (at onset) between the modulated audiovisual stimuli. We discuss our findings in the light of a possible role of direct interactions between early visual and auditory areas, along with contributions from the higher-order association cortex. In sum, our results extend the behavioral evidence of audio-visual processing to the far periphery, and suggest – within this specific experimental setting – an asymmetry between the auditory influence on visual processing and the visual influence on auditory processing.

The abstract is available here: https://uscholar.univie.ac.at/o:1603275

We investigated longitudinal associations of moderate-to-vigorous physical activity (MVPA) and light-intensity physical activity (LPA) with plasma concentrations of 138 metabolites after colorectal cancer (CRC) treatment. Self-reported physical activity data and blood samples were obtained at 6 weeks, and 6, 12 and 24 months post-treatment in stage I-III CRC survivors (n = 252). Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQp180 kit). Linear mixed models were used to evaluate confounder-adjusted longitudinal associations. Inter-individual (between-participant differences) and intra-individual associations (within-participant changes over time) were assessed as percentage difference in metabolite concentration per 5 h/week of MVPA or LPA. At 6 weeks post-treatment, participants reported a median of 6.5 h/week of MVPA (interquartile range:2.3,13.5) and 7.5 h/week of LPA (2.0,15.8). Inter-individual associations were observed with more MVPA being related (FDR-adjusted q-value

Neural oscillations in the theta range (4–8 Hz) are thought to underlie associative memory function in the hippocampal-cortical network. While there is ample evidence supporting a role of theta oscillations in animal and human memory, most evidence is correlational. Non-invasive brain stimulation (NIBS) can be employed to modulate cortical oscillatory activity to influence brain activity, and possibly modulate deeper brain regions, such as hippocampus, through strong and reliable cortico-hippocampal functional connections. We applied focal transcranial alternating current stimulation (tACS) at 6 Hz over left parietal cortex to modulate brain activity in the putative cortico-hippocampal network to influence associative memory encoding. After encoding and brain stimulation, participants completed an associative memory and a perceptual recognition task. Results showed that theta tACS significantly decreased associative memory performance but did not affect perceptual memory performance. These results show that parietal theta tACS modulates associative processing separately from perceptual processing, and further substantiate the hypothesis that theta oscillations are implicated in the cortico-hippocampal network and associative encoding.

Background While single‐omics analyses on human atherosclerotic plaque have been very useful to map stage‐ or disease‐related differences in expression, they only partly capture the array of changes in this tissue and suffer from scale‐intrinsic limitations. In order to better identify processes associated with intraplaque hemorrhage and plaque instability, we therefore combined multiple omics into an integrated model. Methods In this study, we compared protein and gene makeup of low‐ versus high‐risk atherosclerotic lesion segments from carotid endarterectomy patients, as judged from the absence or presence of intraplaque hemorrhage, respectively. Transcriptomic, proteomic, and peptidomic data of this plaque cohort were aggregated and analyzed by DIABLO, an integrative multivariate classification and feature selection method. Results We identified a protein‐gene associated multiomics model able to segregate stable, nonhemorrhaged from vulnerable, hemorrhaged lesions at high predictive performance (AUC >0.95). The dominant component of this model correlated with αSMA−PDGFRα+ fibroblast‐like cell content (p = 2.4E‐05) and Arg1+ macrophage content (p = 2.2E‐04) and was driven by serum response factor (SRF), possibly in a megakaryoblastic leukemia‐1/2 (MKL1/2) dependent manner. Gene set overrepresentation analysis on the selected key features of this model pointed to a clear cardiovascular disease signature, with overrepresentation of extracellular matrix synthesis and organization, focal adhesion, and cholesterol metabolism terms, suggestive of the model's relevance for the plaque vulnerability. Finally, we were able to corroborate the predictive power of the selected features in several independent mRNA and proteomic plaque cohorts. Conclusions In conclusion, our integrative omics study has identified an intraplaque hemorrhage‐associated cardiovascular signature that provides excellent stratification of low‐ from high‐risk carotid artery plaques in several independent cohorts. Further study revealed suppression of an SRF‐regulated disease network, controlling lesion stability, in vulnerable plaque, which can serve as a scaffold for the design of targeted intervention in plaque destabilization., This multiomics analysis identified a cardiovascular signature in carotid atherosclerotic lesions, which provides excellent stratification of low‐/high‐risk carotid plaques.This study highlights the advantages of multiomics analysis in terms of model robustness, biological significance, and clinical translatability.The prediction model pointed to an SRF‐regulated disease network providing valuable new insights that expedite the design of targeted intervention in plaque rupture.

Mutations of the mitochondrial DNA are an important cause of inherited diseases that can severely affect the tissue’s homeostasis and integrity. The m.3243A > G mutation is the most commonly observed across mitochondrial disorders and is linked to multisystemic complications, including cognitive deficits. In line with in vitro experiments demonstrating the m.3243A > G’s negative impact on neuronal energy production and integrity, m.3243A > G patients show cerebral grey matter tissue changes. However, its impact on the most neuron dense, and therefore energy-consuming brain structure—the cerebellum—remains elusive. In this work, we used high-resolution structural and functional data acquired using 7 T MRI to characterize the neurodegenerative and functional signatures of the cerebellar cortex in m.3243A > G patients. Our results reveal altered tissue integrity within distinct clusters across the cerebellar cortex, apparent by their significantly reduced volume and longitudinal relaxation rate compared with healthy controls, indicating macroscopic atrophy and microstructural pathology. Spatial characterization reveals that these changes occur especially in regions related to the frontoparietal brain network that is involved in information processing and selective attention. In addition, based on resting-state functional MRI data, these clusters exhibit reduced functional connectivity to frontal and parietal cortical regions, especially in patients characterized by (i) a severe disease phenotype and (ii) reduced information-processing speed and attention control. Combined with our previous work, these results provide insight into the neuropathological changes and a solid base to guide longitudinal studies aimed to track disease progression.

Background One mechanism that can explain the link between processed meat consumption and colorectal cancer (CRC) is the production of carcinogenic N-nitroso compounds (NOCs) in the gastrointestinal tract. Oral and gut microbes metabolize ingested proteins (a source of secondary and tertiary amines and amides) and can reduce nitrate to nitrite, generating potentially carcinogenic NOCs. Objective We evaluated whether nitrate/nitrite in processed meat or water influences the fecal or salivary microbiota. Design In this dietary intervention study, 63 volunteers consumed diets high in conventional processed meats for two weeks, switched to diets high in poultry for two weeks, and then consumed phytochemical-enriched conventional processed or low-nitrite processed meat diets for two weeks. During the intervention, they drank water with low nitrate concentrations and consumed a healthy diet with low antioxidants. Then the volunteers drank nitrate-enriched water for 1 week, in combination with one of the four different diets. We measured creatinine-adjusted urinary nitrate levels and characterized the oral and fecal microbiota using 16S rRNA amplicon sequencing. Results Using linear mixed models, we found that, compared to baseline, urinary nitrate levels were reduced during the phytochemical-enriched low-nitrite meat diet (p-value = 0.009) and modestly during the poultry diet (p-value = 0.048). In contrast, urinary nitrate increased after 1-week of drinking nitrate-enriched water (p-value