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Chen, C.

Publications and source records attributed to Chen, C..

At least 649 records · Page 36Linked to original sources

Gaining Accuracy for Gene Expression Data by Parsimonious Models

Gene expression data must be accurate in order to promote extensive, reliable, and repeatable results and to compare treatments with few false positives and false negatives. One way to gain accuracy is by advanced experimental techniques, and another is by good experimental design, including replication. But these may not be enough to achieve even one significant digit, as shown by an example using oat data. This article introduces an additional opportunity to increase accuracy that involves parsimonious models, which has not yet been implemented in the gene expression literature to the best of our knowledge. Basically, a parsimonious model gains accuracy by selectively recovering signal in its model while selectively relegating noise to a discarded residual. Typically, this accuracy gain is equivalent to averaging over several times as many replications, but its cost is trivial, merely some computation. Consequently, this neglected way to gain accuracy is quite cost effective. For gene expression research, accuracy gain by parsimonious models should be a standard component of best practices.

genetics↗

Interactive MS/MS Visualization with the Metabolomics Spectrum Resolver Web Service

The growth of online mass spectrometry metabolomics resources, including data repositories, spectral library databases, and online analysis platforms has created an environment of online/web accessibility. Here, we introduce the Metabolomics Spectrum Resolver (https://metabolomics-usi.ucsd.edu/), a tool that builds upon these exciting developments to allow for consistent data export (in human and machine-readable forms) and publication-ready visualisations of tandem mass spectrometry spectra. This tool supports the Human Proteome Organization - Proteomics Standards Initiatives Universal Spectrum Identifier (USI) specification, which has been extended to deal with the metabolomics use cases. To date, this resource already supports data formats from GNPS, MassBank, MS2LDA, MassIVE, MetaboLights, and Metabolomics Workbench and is integrated into several of these resources.

bioinformatics↗

Therapeutic remodeling of CBP transcription factor complex controls oncogenic gene expression in acute myeloid leukemia

Dysregulated gene expression contributes to most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300 co-activation of a distinct set of transcription factor complexes. These MYB complexes assemble aberrantly with LYL1, E2A, C/EBP family members, LMO2 and SATB1. They are organized convergently in genetically diverse subtypes of AML, and are at least in part associated with inappropriate transcription factor co-expression. Peptidomimetic remodeling of oncogenic MYB complexes is accompanied by specific proteolysis and dynamic redistribution of CBP/P300 with alternative transcription factors such as RUNX1 to induce myeloid differentiation and apoptosis. Thus, aberrant assembly and sequestration of MYB:CBP/P300 complexes provide a unifying mechanism of oncogenic gene expression in AML. This work establishes a compelling strategy for their pharmacologic reprogramming and therapeutic targeting for diverse leukemias and possibly other human cancers caused by dysregulated gene control.

cancer biology↗

Prediction of protein-protein interactions based on elastic net and deep forest

Prediction of protein-protein interactions (PPIs) helps to grasp molecular roots of disease. However, web-lab experiments to predict PPIs are limited and costly. Using machine-learning-based frameworks can not only automatically identify PPIs, but also provide new ideas for drug research and development from a promising alternative. We present a novel deep-forest-based method for PPIs prediction. First, pseudo amino acid composition (PAAC), autocorrelation descriptor (Auto), multivariate mutual information (MMI), composition-transition-distribution (CTD), and amino acid composition PSSM (AAC-PSSM), and dipeptide composition PSSM (DPC-PSSM) are adopted to extract and construct the pattern of PPIs. Secondly, elastic net is utilized to optimize the initial feature vectors and boost the predictive performance. Finally, GcForest-PPI model based on deep forest is built up. Benchmark experiments reveal that the accuracy values of Saccharomyces cerevisiae and Helicobacter pylori are 95.44% and 89.26%. We also apply GcForest-PPI on independent test sets and CD9-core network, crossover network, and cancer-specific network. The evaluation shows that GcForest-PPI can boost the prediction accuracy, complement experiments and improve drug discovery. The datasets and code of GcForest-PPI could be downloaded at https://github.com/QUST-AIBBDRC/GcForest-PPI/.

bioinformatics↗

MINERVA: A facile strategy for SARS-CoV-2 whole genome deep sequencing of clinical samples

The novel coronavirus disease 2019 (COVID-19) pandemic poses a serious public health risk. Analyzing the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from clinical samples is crucial for the understanding of viral spread and viral evolution, as well as for vaccine development. Existing sample preparation methods for viral genome sequencing are demanding on user technique and time, and thus not ideal for time-sensitive clinical samples; these methods are also not optimized for high performance on viral genomes. We have developed MetagenomIc RNA EnRichment VirAl sequencing (MINERVA), a facile, practical, and robust approach for metagenomic and deep viral sequencing from clinical samples. This approach uses direct tagmentation of RNA/DNA hybrids using Tn5 transposase to greatly simplify the sequencing library construction process, while subsequent targeted enrichment can generate viral genomes with high sensitivity, coverage, and depth. We demonstrate the utility of MINERVA on pharyngeal, sputum and stool samples collected from COVID-19 patients, successfully obtaining both whole metatranscriptomes and complete high-depth high-coverage SARS-CoV-2 genomes from these clinical samples, with high yield and robustness. MINERVA is compatible with clinical nucleic extracts containing carrier RNA. With a shortened hands-on time from sample to virus-enriched sequencing-ready library, this rapid, versatile, and clinic-friendly approach will facilitate monitoring of viral genetic variations during outbreaks, both current and future.

molecular biology↗

Weight Sensitivity of Temporal SNR Metrics in multi-echo fMRI

PurposeIn multi-echo fMRI (ME-fMRI), various weighting schemes have been proposed for the combination of the data across echoes. Here we introduce a framework that facilitates a deeper understanding of the weight dependence of temporal SNR measures in ME-fMRI. Theory and MethodsWe examine two metrics that have been used to characterize ME-fMRI performance: temporal SNR (tSNR) and multi-echo temporal (metSNR). Both metrics can be described using the generalized Rayleigh quotient (GRQ) and are predicted to be relatively insensitive to the weights when there is a high degree of similarity between a metric-specific matrix in the GRQ numerator and a metricindependent covariance matrix in the GRQ denominator. The application of the GRQ framework to experimental data is demonstrated using a resting-state fMRI dataset acquired with a multi-echo multi-band EPI sequence. ResultsIn the example dataset, similarities between the covariance matrix and the metSNR and tSNR numerator matrices are highest in grey matter (GM) and cerebrospinal fluid (CSF) voxels, respectively. For representative GM and CSF voxels that exhibit high matrix similarity values, the metSNR and tSNR values, respectively, are both within 4% of their optimal values across a range of weighting schemes. However, there is a fundamental tradeoff, with a high degree of weight sensitivity in the tSNR and metSNR metrics for the representative GM and CSF voxels, respectively. Geometric insight into the observed weight dependencies is provided through a graphical interpretation of the GRQ. ConclusionA GRQ framework can provide insight into the factors that determine the weight sensitivity of tSNR and metSNR measures in ME-fMRI.

neuroscience↗

The beginning of the end: a chromosomal assembly of the New World malaria mosquito ends with a novel telomere

Chromosome level assemblies are accumulating in various taxonomic groups including mosquitoes. However, even in the few reference-quality mosquito assemblies, a significant portion of the heterochromatic regions including telomeres remain unresolved. Here we produce a de novo assembly of the New World malaria mosquito, Anopheles albimanus by integrating Oxford Nanopore sequencing, Illumina, Hi-C and optical mapping. This 172.6 Mbps female assembly, which we call AalbS3, is obtained by scaffolding polished large contigs (contig N50=13.7 Mbps) into three chromosomes. All chromosome arms end with telomeric repeats, which is the first in mosquito assemblies and represents a significant step towards the completion of a genome assembly. These telomeres consist of tandem repeats of a novel 30-32 bp telomeric repeat unit (TRU) and are confirmed by analysing the termini of long reads and through both chromosomal in situ hybridization and a Bal31 sensitivity assay. The AalbS3 assembly included previously uncharacterized centromeric and rDNA clusters and more than doubled the content of transposable elements and other repetitive sequences. This telomere-to-telomere assembly, although still containing gaps, represents a significant step towards resolving biologically important but previously hidden genomic components. The comparison of different scaffolding methods will also inform future efforts to obtain reference-quality genomes for other mosquito species. 100-word Article SummaryWe report AalbS3, a telomere-to-telomere assembly of the Anopheles albimanus genome produced by integrating advancing technologies including Oxford Nanopore and Bionano optical mapping. AalbS3 features much of the difficult-to-assemble genomic dark matters including previously missed transposons, centromeres and rDNA clusters. We describe novel telomeric repeats that are confirmed by analysis of long reads and by telomere hybridization assays. This reference-quality assembly represents a significant step towards completing the genomic puzzle pieces and informs efforts to improve the assembly of other mosquito species. Future research into the relationship between telomere and mosquito life span may have significant implications to disease control.

genomics↗

Role of short-chain fatty acids in the gut-brain axis in schizophrenia: contribution to immune activation and pathophysiology in humans and mice

ObjectiveGut microbiota dysbiosis and aberrant gut-brain functional modules including short-chain fatty acid (SCFA) production and long-lasting immune activation (IA) are presented in schizophrenia. Given the key roles of gut microbiota and SCFA in shaping immunity, we propose that dysbiosis-induced SCFA upregulation could contribute to IA and behavioral symptoms in schizophrenia. DesignGut microbiota, SCFA, and IA biomarkers were compared between schizophrenic patients and healthy controls. The roles of SCFA in schizophrenia-related IA were analyzed in cultured peripheral blood mononuclear cells (PBMCs) and a mouse model of schizophrenia. The effects of SCFAs on schizophrenia-related phenotypes were analyzed in both human and mouse. ResultsBoth microbial-derived SCFA and SCFA-producing bacteria were elevated in the guts of schizophrenic patients, and this increased SCFA production in gut was associated with IA in schizophrenia. The microbiome signature underpinning schizophrenia-related IA includes increased diversity and increased SCFA-producing bacteria and inflammation-associated bacteria. The impact of SCFAs on immune responses of cultured PBMC depend on the diagnosis and IA status of donors. Small-molecule serum filtrates from immune-activated schizophrenic patients increased the inflammatory response of PBMCs from healthy volunteers, which can be enhanced and attenuated by SCFAs supplementation and inhibition of SCFA signaling, respectively. Chronically elevated SCFAs in adolescence induced neuroinflammation and schizophrenia-like behaviors in adult mice. Moreover, chronically elevated SCFAs in adult mice prenatally exposed to IA potentiated their expression of schizophrenia-like behaviors. Conclusionmicrobiota-derived SCFAs are important mediators of dysregulated gut-brain axis and participant in pathogenesis via enhance IA in schizophrenia. SummaryO_ST_ABSSignificance of this studyC_ST_ABSO_LIWhat is already known about this subject? [tpltrtarr]Schizophrenia pathogenesis goes beyond the brain since increasing peripheral abnormalities are revealed including gut microbiota dysbiosis, GI dysfunction, and systemic immune activation (IA). [tpltrtarr]Systemic IA/inflammation contributes to the neuroinflammation and brain impairment underlying schizophrenia, and adjunctive immunotherapy can improve psychotic symptoms. [tpltrtarr]Short-chain fatty acids (SCFA) mediate the microbiota-gut-brain communication and modulate several pathways involved in schizophrenia, including pathways of immunity and neurotransmitters. C_LIO_LIWhat are the new findings? [tpltrtarr]Patients with schizophrenia displayed increased rates of IA and increased SCFA production compared with healthy controls, and increased SCFA is associated with IA in patients. [tpltrtarr]A unique microbiota signature including enriched SCFA-producing bacterial species can distinguish patients with IA from other patients and controls. [tpltrtarr]Small molecules in the serum of immune-activated patients with schizophrenia enhance LPS-induced immune response of cultured peripheral blood mononuclear cell (PBMCs), which is partially mediated by SCFA signaling. [tpltrtarr]SCFA intake upregulates both peripheral and brain inflammation and potentiates the expression of schizophrenia-like behaviors in mice prenatally exposed to IA. C_LIO_LIHow might it impact on clinical practice in the foreseeable future? [tpltrtarr]Interference of SCFA signaling or targeted destruction of SCFA-producing bacteria may provide a new approach for the prevention and treatment of schizophrenia. [tpltrtarr]Immune activation status of patients should be an important condition considered when selecting immunotherapy for future precision psychiatric therapy. C_LI

neuroscience↗

Distinct target-specific mechanisms homeostatically stabilize transmission at pre-and post-synaptic compartments

Neurons must establish and stabilize connections made with diverse targets, each with distinct demands and functional characteristics. At Drosophila neuromuscular junctions, synaptic strength remains stable in a manipulation that simultaneously induces hypo-innervation on one target and hyper-innervation on the other. However, the expression mechanisms that achieve this exquisite target-specific homeostatic control remain enigmatic. Here, we identify the distinct target-specific homeostatic expression mechanisms. On the hypo-innervated target, an increase in postsynaptic glutamate receptor (GluR) abundance is sufficient to compensate for reduced innervation, without any apparent presynaptic adaptations. In contrast, a target-specific reduction in presynaptic neurotransmitter release probability is reflected by a decrease in active zone components restricted to terminals of hyper-innervated targets. Finally, loss of postsynaptic GluRs on one target induces a compartmentalized, homeostatic enhancement of presynaptic neurotransmitter release called presynaptic homeostatic potentiation that can be precisely balanced with the adaptations required for both hypo- and hyper-innervation to maintain stable synaptic strength. Thus, distinct anterograde and retrograde signaling systems operate at pre- and post-synaptic compartments to enable target-specific, homeostatic control of neurotransmission.

neuroscience↗

Risperidone-induced changes in DNA methylation from peripheral blood in first-episode schizophrenia parallel neuroimaging and cognitive phenotype

Today, second generation anti-psychotics such as clozapine and risperidone are the favored treatment for schizophrenia. Yet, the absence of relevant biomarkers that can decode their neurobiological effect shackles our ability to accurately predict and track response to treatment. While researchers have investigated DNA methylation as a biomarker for schizophrenia risk, none have performed a systematic analysis of the effect of antipsychotics upon DNA methylation. We hypothesize that disease-related methylation changes occur before treatment, and that acute antipsychotic treatment may affect DNA methylation. We designed a longitudinal DNA methylation study to estimate risperidones effect on DNA methylation and how changes in DNA methylation might influence risperidones therapeutic effect on behavioral and neuroimaging phenotypes. Thirty-eight patients with first-episode drug-naive schizophrenia (FES) and 38 demographically-matched individuals (healthy controls) participated. We identified brain related pathways enriched in 8,204 FES-associated methylation sites. Risperidone administration altered methylation in 6,143 CpG DNA sites. Post-treatment FES associated with methylation in 6760 CpG sites. Majority of the DNA methylation changes were treatment effect in the overall CpG sites, the FES associated CpG sites, and risperidone associated CpG sites, except for the post-treatment FES associated CpG sites. There were 590 DNA methylation cites normalized by risperidone treatment. The methylation changes of these 590 CpG sites were related to alterations in symptom severity, spontaneous neurophysiological activity, and cognitive function. To our knowledge, this is the first longitudinal methylation study of drug treatment effect and side effect in psychiatric disorders to include parallel studies of neuroimaging and cognitive phenotypes. We identified FES-associated CpG sites not confounded by drug treatment as potential SCZ biomarkers. The normalization effect of risperidone monotherapy suggests that DNA methylation changes may serve as a predictive biomarker for treatment effect. The constructed methylation-phenotype network revealed a relationship between methylation and a wide range of biological and psychological variables.

pharmacology and toxicology↗

Unmasking Anxiety in Autism: Explicit and Implicit Threatening Face Stimuli Dissociate Amygdala-centered Functional Connectivity

BackgroundAnxiety is the most prevalent comorbidity in individuals diagnosed with autism spectrum disorder (ASD). Amygdala reactivity to explicit and implicit threat processing is predictive of anxiety-related symptomatology. The neural mechanisms underlying the link between anxiety and ASD remains elusive. MethodsIn this fMRI study, we recruited young adults with ASD (N = 31) and matched them with controls, then proceeded to assess their autistic and anxiety traits by the use of the Autism-Spectrum Quotient (AQ) and the State-Trait Anxiety Inventory (STAI-S), respectively; and scanned their hemodynamic responses, including amygdala, in response to explicit and implicit (backwardly masked) perception of threatening faces. ResultsAs compared to controls, the amygdala reactivity in ASD subjects was significantly lower to explicit threat, but comparable for implicit threat. The correlations of the amygdala reactivity with the AQ and STAI-S were dissociated depending on threat processing (explicit or implicit). Furthermore, the amygdala in ASD relative to controls had a more negative functional connectivity with the superior parietal cortex, fusiform gyrus, and hippocampus for explicit threat, whereas a more positive connectivity with the medial prefrontal cortex, temporal pole, and hippocampus for implicit threat. ConclusionIn ASD, the transmission of socially relevant information along dorsal and ventral neural pathways centered on the amygdala is dissociated depending on explicit and implicit threat processing. This dissociation, ascribed to their failure to compromise pre-existing hyperarousal, might contribute to anxiety in ASD.

neuroscience↗

A Comprehensive Survey of Mutations in Oesophageal Carcinoma Reveals Recurrent Neoantigens as Potential Immunotherapy Targets

This study was aimed to investigate the mutations in Esophageal Carcinoma (EC) for recurrent neoantigen identification. A total of 733 samples with whole exome sequencing (WES) mutation data and 1153 samples with target region sequencing data were obtained from 7 published studies and GENIE database. Common HLA-I and HLA-II genotypes in both TCGA cohort and Chinese were used to predict the probability of public neoantigens in the dataset. Based on the integrated data, we not only obtained the most comprehensive EC mutation landscape so far, but also found 253 mutation sites which could be identified in at least 3 or more patients, including, TP53 p.R248Q, PIK3CA p.E545K, PIK3CA p.E542K, KRAS p.G12D, PIK3CA p.H1047R and TP53 p.C83F. These mutations can be recognized by multiple common HLA molecules (HLA-A11:01, HLA-B57:01, HLA-A03:01, DRB1-0301, DRB1-1202, et al.) in Chinese and TCGA cohort as potential public neoantigens. Overall, our analysis provides some potential targets for EC immunotherapy.

immunology↗

Soybean Yellow Stripe-like7 is a symbiosome membrane peptide transporter essential for nitrogen fixation

Legumes form a symbiosis with rhizobia that convert atmospheric nitrogen (N2) to ammonia which they provide to the plant in return for a carbon and nutrient supply. Nodules, developed as part of the symbiosis, harbor rhizobia which are enclosed in the plant-derived symbiosome membrane (SM), to form a symbiosome. In the mature nodule all exchanges between the symbionts occur across the SM. Here we characterize GmYSL7, a member of Yellow stripe-like family which is localized to the SM in soybean nodules. It is expressed specifically in nodule infected cells with expression peaking soon after nitrogenase becomes active. Although most members of the family transport metal complexed with phytosiderophores, GmYSL7 does not. It transports oligopeptides of between four and 12 amino acids. Silencing of GmYSL7 reduces nitrogenase activity and blocks development when symbiosomes contain a single bacteroid. RNAseq of nodules in which GmYSL7 is silenced suggests that the plant initiates a defense response against the rhizobia. There is some evidence that metal transport in the nodules is dysregulated, with upregulation of genes encoding ferritin and vacuolar iron transporter family and downregulation of a gene encoding nicotianamine synthase. However, it is not clear whether the changes are a result of the reduction of nitrogen fixation and the requirement to store excess iron or an indication of a role of GmYSL7 in regulation of metal transport in the nodules. Further work to identify the physiological substrate for GmYSL7 will allow clarification of this role. One sentence summaryGmYSL7 is a symbiosome membrane peptide transporter that is essential for symbiotic nitrogen fixation that when silenced blocks symbiosome development.

plant biology↗

Large-scale Phenotypic Drug Screen Identifies Neuroprotectants in Zebrafish and Mouse Models of Retinitis Pigmentosa

Retinitis pigmentosa (RP) and associated inherited retinal diseases (IRDs) are caused by rod photoreceptor degeneration, necessitating therapeutics promoting rod photoreceptor survival. To address this, we tested compounds for neuroprotective effects in zebrafish and mouse RP models, reasoning drugs effective across species may translate better clinically. We first performed a large-scale phenotypic drug screen using a larval zebrafish model of inducible RP. 2,934 compounds, mostly human-approved drugs, were tested across six concentrations. Statistically, 113 compounds achieved "hit" status. Secondary tests of 42 high-priority hits confirmed eleven lead compounds. Nine leads were then evaluated in mouse RP models, with six exhibiting neuroprotective effects. An analysis of potential mechanisms of action suggested complementary activities. Paired lead compound assays in zebrafish showed additive neuroprotective effects for the majority. These results highlight the value of cross-species phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for patients with RP and IRDs.

neuroscience↗

A temperature-dependent molecular switch to adjust behavior to changing environmental conditions

Daily temporal organisation of behavioural and physiological functions offers a fitness advantage for most animals. Optimized temporal niches are determined by an interplay between external environmental rhythms and internal circadian clocks. While daily light:dark cycles serve as a robust time cue (Zeitgeber) to synchronise circadian clocks, it is not clear how animals experiencing only weak environmental cues deal with this problem. Like humans, flies of the genus Drosophila originate in sub-Saharan Africa and spread North in Europe up to the polar circle where they experience extremely long days in the summer or even constant light (LL). LL is known to disrupt clock function, due to constant activation of the deep brain photoreceptor CRYPTOCHROME (CRY), which induces constant degradation of the clock protein TIMELESS (TIM). Temperature cycles are able to overcome these arrhythmia inducing effects of LL, reinstating clock protein oscillations and rhythmic behaviour. We show here that for this to occur a recently evolved natural allele (ls-tim) of the timeless gene is required, whereby the presence of this allele within the central clock neurons is sufficient. The ls-tim allele encodes a longer, less-light sensitive form of TIM (L-TIM) in addition to the shorter (S-TIM) form, the only form encoded by the ancient s-tim allele. Only after blocking light-input by removing functional CRY, s-tim flies are able to synchronise molecular and behavioural rhythms to temperature cycles in LL. Additional removal of light input from the visual system results in a phase advance of molecular and behavioural rhythms, showing that the visual system contributes to temperature synchronization in LL. We show that ls-tim, but not s-tim flies can synchronise their behavioural activity to semi-natural LL and temperature cycle conditions reflecting long Northern Europe summer days, the season when Drosophila populations massively expand. Our observations suggest that this functional gain associated with ls-tim is driving the Northern spread of this allele by directional selection.

neuroscience↗

Automated design and optimization of multitarget schizophrenia drug candidates by deep learning

Complex neuropsychiatric diseases such as schizophrenia require drugs that can target multiple G protein-coupled receptors (GPCRs) to modulate complex neuropsychiatric functions. Here, we report an automated system comprising a deep recurrent neural network (RNN) and a multitask deep neural network (MTDNN) to design and optimize multitargeted antipsychotic drugs. The system successfully generates novel molecule structures with desired multiple target activities, among which high-ranking compound 3 was synthesized, and demonstrated potent activities against dopamine D2, serotonin 5-HT1A and 5-HT2A receptors. Hit expansion based on the MTDNN was performed, 6 analogs of compound 3 were evaluated experimentally, among which compound 8 not only exhibited specific polypharmacology profiles but also showed antipsychotic effect in animal models with low potential for sedation and catalepsy, highlighting their suitability for further preclinical studies. The approach can be an efficient tool for designing lead compounds with multitarget profiles to achieve the desired efficacy in the treatment of complex neuropsychiatric diseases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC="FIGDIR/small/999615v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@17046d8org.highwire.dtl.DTLVardef@3b4c2aorg.highwire.dtl.DTLVardef@10590e9org.highwire.dtl.DTLVardef@6cc609_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

Genome architecture and transcription data reveal allelic bias during the cell cycle

Every human somatic cell inherits a maternal and a paternal genome, which work together to give rise to cellular phenotypes. However, the allele-specific relationship between gene expression and genome structure through the cell cycle is largely unknown. By integrating haplotype-resolved genome-wide chromosome conformation capture, mature and nascent mRNA, and protein binding data, we investigate this relationship both globally and locally. We introduce the maternal and paternal 4D Nucleome, enabling detailed analysis of the mechanisms and dynamics of genome structure and gene function for diploid organisms. Our analyses find significant coordination between allelic expression biases and local genome conformation, and notably absent expression bias in universally essential cell cycle and glycolysis genes. We propose a model in which coordinated biallelic expression reflects prioritized preservation of essential gene sets.

bioinformatics↗

Selective gating of retinal information by arousal

How sensory information is processed by the brain can depend on behavioral state. In the visual thalamus and cortex, arousal/locomotion is associated with changes in the magnitude of responses to visual stimuli. Here, we asked whether such modulation of visual responses might already occur at an earlier stage in this visual pathway. We measured neural activity of retinal axons using wide-field and two-photon calcium imaging in awake mouse thalamus across arousal states associated with different pupil sizes. Surprisingly, visual responses to drifting gratings in retinal axonal boutons were robustly modulated by arousal level, in a manner that varied across stimulus dimensions and across functionally distinct subsets of boutons. At low and intermediate spatial frequencies, the majority of boutons were suppressed by arousal. In contrast, at high spatial frequencies, the proportions of boutons showing enhancement or suppression were more similar, particularly for boutons tuned to regions of visual space ahead of the mouse. Arousal-related modulation also varied with a boutons sensitivity to luminance changes and direction of motion, with greater response suppression in boutons tuned to luminance decrements vs. increments, and in boutons preferring motion along directions or axes of optic flow. Together, our results suggest that differential filtering of distinct visual information channels by arousal state occurs at very early stages of visual processing, before the information is transmitted to neurons in visual thalamus. Such early filtering may provide an efficient means of optimizing central visual processing and perception of state-relevant visual stimuli.

neuroscience↗