Biology subjects

Wang, E.

Publications and source records attributed to Wang, E..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Proteomic signaling of dual specificity phosphatase 4 (DUSP4) in Alzheimer's disease

DUSP4 is a member of the DUSP (Dual-Specificity Phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimers disease (AD). In this study, we utilized stereotactic delivery of adeno-associated virus (AAV)-DUSP4 to overexpress DUSP4 in the dorsal hippocampus of 5xFAD and wildtype (WT) mice, then used mass spectrometry (MS)-based proteomics along with label-free quantification to profile the proteome and phosphoproteome in the hippocampus. We identified patterns of protein expression and phosphorylation that are modulated in 5xFAD mice and examined the sex-specific impact of DUSP4 overexpression on the 5xFAD proteome/phosphoproteome. In 5xFAD mice, a substantial number of proteins were up- or down-regulated in both male and female mice in comparison to age and sex-matched WT mice, many of which are involved in AD-related biological processes, such as the activated immune response or suppression of synaptic activities. Upon DUSP4 overexpression, significantly regulated proteins were found in pathways that were suppressed, such as the immune response, in male 5xFAD mice. In contrast, such a shift was absent in female mice. For the phosphoproteome, we detected an array of phosphorylation sites that are regulated in 5xFAD compared to WT, and are modulated by DUSP4 overexpression in each sex. Interestingly, the changes in 5xFAD- and DUSP4-associated phosphorylation occurred in opposite directions. Strikingly, both the 5xFAD- and DUSP4-associated phosphorylation changes were found for the most part in neurons, and play key roles in neuronal processes and synaptic function. Site-centric pathway analysis revealed that both the 5xFAD- and DUSP4-associated phosphorylation sites were enriched for a number of kinase sets in female, but only a limited number of sets of kinases in male mice. Taken together, our results suggest that male and female 5xFAD mice respond to DUSP4 overexpression via shared and sex-specific molecular mechanisms, which might underly similar reductions in amyloid pathology in both sexes, while learning deficits were reduced in only females with DUSP4 overexpression. Finally, we validated our findings with the sex-specific AD-associated proteomes in human cohorts and further developed DUSP4-centric proteomic network models and signaling maps for each sex.

bioinformatics↗

bioRxiv2023

Enlarged Perivascular Spaces are Associated with White Matter Injury, Brain Atrophy, Cognitive Decline and Markers of Inflammation in an Autosomal Dominant Vascular Neurodegenerative Disease (CADASIL)

Background and ObjectivesEnlarged perivascular spaces (ePVS) have been previously reported in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL), but their significance and pathophysiology remains unclear. We investigated associations of ePVS with classical imaging measures, cognitive measures and plasma proteins to better understand what ePVS represents in CADASIL and whether radiographic measures of ePVS would be of value in future therapeutic discovery studies for CADASIL. Methods24 individuals with CADASIL and 24 age and sex matched controls were included. Disease status was determined based on presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity (WMH), brain parenchymal fraction (BPF), ePVS volumes, clinical, and cognitive measures, as well as plasma proteomics were used in models. Global ePVS volumes were calculated via a novel, semi-automated pipeline and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of ePVS with global burden of WMH, brain atrophy, functional status, neurocognitive measures, and plasma proteins were modelled with linear regression models. ResultsCADASIL and control groups did not exhibit differences in mean ePVS volumes. However, increased ePVS volumes in CADASIL were associated with increased WMH volume ({beta}=0.57, p=0.05), Clinical Dementia Rating (CDR) Sum-of-Boxes score ({beta}=0.49, p=0.04), and decreased brain parenchymal fraction (BPF) ({beta}=-0.03, p=0.10). In interaction term models, the interaction term between CADASIL disease status and ePVS volume was associated with increased WMH volume ({beta}=0.57, p=0.02), Clinical Dementia Rating (CDR) Sum-of-Boxes score ({beta}=0.52, p=0.02), decreased BPF ({beta}=-0.03, p=0.07) and Mini Mental State Examination (MMSE) score ({beta}=-1.49, p=0.03). Proteins positively associated with ePVS volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with ePVS volumes: CXCL8/IL-8, and CCL2/MCP-1. The levels of CXCL8/IL8 were also associated with increased WMH volume ({beta}=2.44, p < 0.01), and levels of CCL2/MCP-1 were further associated with decreased BPF ({beta}=-0.0007, p < 0.01), MMSE score ({beta}=-0.02, p < 0.01), and increased Trail Making Test B (TRAILB) completion time ({beta}=0.76, p < 0.01). No protein was associated with all 3 studied imaging measures of pathology (BPF,ePVS,WMH). DiscussionBased on associations uncovered between ePVS volumes and cognitive functions, imaging and plasma proteins, we conclude that ePVS volumes capture pathologies contributing to chronic brain dysfunction and degeneration in CADASIL, with relevance to future clinical trials for novel therapeutic discoveries to prevent decline and injury in individuals carrying NOTCH3 mutations.

neuroscience↗

bioRxiv2023

The Shank/ProSAP N-terminal (SPN) domain of Shank3 regulates targeting to postsynaptic sites and postsynaptic signalling.

Members of the Shank family of postsynaptic scaffold proteins (Shank1-3) link neurotransmitter receptors to the actin cytoskeleton in dendritic spines through establishing numerous interactions within the postsynaptic density (PSD) of excitatory synapses. Large Shank isoforms carry at their N-termini a highly conserved domain termed the Shank/ProSAP N-terminal (SPN) domain, followed by a set of ankyrin repeats. Both domains are involved in an intramolecular interaction which is believed to regulate accessibility for additional interaction partners, such as Ras family G-proteins, CaMKII and cytoskeletal proteins. Here we analyse the functional relevance of the SPN-Ank module; we show that binding of active Ras or Rap1a to the SPN domain can differentially regulate the localization of Shank3 in dendrites. In Shank1 and Shank3, the linker between the SPN and Ank domains binds to inactive CaMKII. Due to this interaction, both Shank1 and Shank3 exert a negative effect on CaMKII activity at postsynaptic sites in mice in vivo. The relevance of the SPN-Ank intramolecular interaction was further analysed in primary cultured neurons; here we observed that in the context of full-length Shank3, a closed conformation of the SPN-Ank tandem is necessary for proper clustering of Shank3 on the head of dendritic spines. Shank3 variants carrying Ank repeats which are not associated with the SPN domain lead to the atypical formation of postsynaptic clusters on dendritic shafts, at the expense of dendritic spines. Our data show that the SPN-Ank tandem motif contributes to the regulation of postsynaptic signalling, and is also necessary for proper targeting of Shank3 to postsynaptic sites. Our data also suggest how missense variants found in autistic patients which alter SPN and Ank domains affect the synaptic function of Shank3.

neuroscience↗

bioRxiv2023

Comparative Phylogenomics and Phylotranscriptomics Provide Insights into the Genetic Complexity of Nitrogen Fixing Root Nodule Symbiosis

Plant root nodule symbiosis (RNS) with mutualistic nitrogen-fixing bacteria is restricted to a single clade of angiosperms, the Nitrogen-Fixing Nodulation Clade (NFNC), and is best understood in the legume family. It is widely accepted that nodulation originated through the assembly of modules recruited from existing functions, such as mycorrhizal symbiosis, polar growth, and lateral root development. Because nodulating species are scattered within the NFNC, the number of times nodulation has evolved or has been lost has been a matter of considerable speculation. This interesting evolutionary question has practical implications concerning the ease with which nodulation might be engineered in non-nodulating crop plants. Nodulating species share many commonalities, due either to divergence from a common ancestor over 100 million years ago or to convergence or deep homology following independent origins over that same time period. In either case, comparative analyses of diverse nodulation syndromes can provide insights into constraints on nodulation--what must be acquired or cannot be lost for a functional symbiosis--and what the latitude is for variation in the symbiosis. However, much remains to be learned about nodulation, especially outside of legumes. Here we present new information across the spectrum of nodulating groups. We find no evidence for convergence at the level of amino acid residues or gene family expansion across the NFNC. Our phylogenomic analyses further emphasize the uniqueness of the transcription factor, NIN, as a master regulator of nodulation, and identify key mutations affecting its function across the NFNC. We find that nodulation genes are over-represented among orthologous gene groups (OGs) present in the NFNC common ancestor, but that lineage-specific OGs play major roles in nodulation. We identified over 900,000 conserved noncoding elements (CNEs), of which over 300,000 were unique to NFNC species. A significant proportion of these are associated with nodulation-related genes and thus are candidates for transcriptional regulators.

evolutionary biology↗

bioRxiv2023

Genome-wide characterization of T cell responses to Bordetella pertussis reveals broad reactivity and similar polarization irrespective of childhood vaccination profiles.

The incidence of whooping cough (pertussis), the respiratory disease caused by Bordetella pertussis (BP) has increased in recent years, and it is suspected that the switch from whole-cell pertussis (wP) to acellular pertussis (aP) vaccines may be a contributing factor to the rise in morbidity. While a growing body of evidence indicates that T cells play a role in the control and prevention of symptomatic disease, nearly all data on human BP-specific T cells is related to the four antigens contained in the aP vaccines, and data detailing T cell responses to additional non-aP antigens, are lacking. Here, we derived a full-genome map of human BP-specific CD4+ T cell responses using a high-throughput ex vivo Activation Induced Marker (AIM) assay, to screen a peptide library spanning over 3000 different BP ORFs. First, our data show that BP specific-CD4+ T cells are associated with a large and previously unrecognized breadth of responses, including hundreds of targets. Notably, fifteen distinct non-aP vaccine antigens were associated with reactivity comparable to that of the aP vaccine antigens. Second, the overall pattern and magnitude of CD4+ T cell reactivity to aP and non-aP vaccine antigens was similar regardless of aP vs wP childhood vaccination history, suggesting that the profile of T cell reactivity in adults is not driven by vaccination, but rather is likely driven by subsequent asymptomatic or sub-clinical infections. Finally, while aP vaccine responses were Th1/Th2 polarized as a function of childhood vaccination, CD4+ T cell responses to non-aP BP antigens vaccine responses were not, suggesting that these antigens could be used to avoid the Th2 bias associated with aP vaccination. Overall, these findings enhance our understanding of human T cell responses against BP and suggest potential targets for designing next-generation pertussis vaccines.

immunology↗

bioRxiv2023

Bipartite invariance in mouse primary visual cortex

A primary goal of sensory systems is to extract robust and meaningful features that are invariant to variations in the sensory input. Characterizing these invariances at the neuronal level is crucial for understanding how the visual system supports generalization, but the high-dimensional nature of ecological stimuli poses major challenges. Consequently, our understanding of how the brain represents invariances has historically depended on a few examples, such as phase invariance to grating stimuli in V1 complex cells. Here, we leverage the inception loop paradigm --iterating between large-scale recordings, deep learning neuronal predictive models, and in silico experiments with in vivo verification--to characterize neuronal invariances in mouse V1. Using a neuronal predictive model, we synthesized Diverse Exciting Inputs (DEIs) that strongly drive target neurons while differing substantially in image space. These DEIs revealed a novel bipartite invariance: one portion of the receptive field encodes shift-invariant, high-frequency textures, while the other encodes a fixed, low-frequency spatial pattern. This subfield division aligned with object boundaries defined by spatial frequency differences in highly activating stimuli, suggesting bi-partite invariance contributes to segmentation. Our analysis of computational models and anatomical data from the MICrONS dataset revealed a hierarchical organization of excitatory neurons in mouse V1 Layers 2/3: We found that postsynaptic neurons exhibited greater invariance than their presynaptic inputs, while neurons with lower invariance formed more connections. These findings suggest a synaptic-level hierarchy that progressively increases neural invariance within the primary visual cortex. Intriguingly, similar high-low frequency bipartite patterns strongly activate certain units in artificial neural networks, suggesting that universal visual representations govern both biological and artificial systems, potentially aiding in the extraction of visual features from complex backgrounds.

neuroscience↗

bioRxiv2023

NEURD: A mesh decomposition framework forautomated proofreading and morphologicalanalysis of neuronal EM reconstructions

We are now in the era of millimeter-scale electron microscopy (EM) volumes collected at nanometer resolution (Shapson-Coe et al., 2021; Consortium et al., 2021). Dense reconstruction of cellular compartments in these EM volumes has been enabled by recent advances in Machine Learning (ML) (Lee et al., 2017; Wu et al., 2021; Lu et al., 2021; Macrina et al., 2021). Automated segmentation methods produce exceptionally accurate reconstructions of cells, but post-hoc proofreading is still required to generate large connectomes free of merge and split errors. The elaborate 3-D meshes of neurons in these volumes contain detailed morphological information at multiple scales, from the diameter, shape, and branching patterns of axons and dendrites, down to the fine-scale structure of dendritic spines. However, extracting these features can require substantial effort to piece together existing tools into custom workflows. Building on existing open-source software for mesh manipulation, here we present "NEURD", a software package that decomposes meshed neurons into compact and extensively-annotated graph representations. With these feature-rich graphs, we automate a variety of tasks such as state of the art automated proofreading of merge errors, cell classification, spine detection, axon-dendritic proximities, and other annotations. These features enable many downstream analyses of neural morphology and connectivity, making these massive and complex datasets more accessible to neuroscience researchers focused on a variety of scientific questions.

neuroscience↗

bioRxiv2023

Functional connectomics reveals general wiring rule in mouse visual cortex

Understanding the relationship between circuit connectivity and function is crucial for uncovering how the brain implements computation. In the mouse primary visual cortex (V1), excitatory neurons with similar response properties are more likely to be synaptically connected, but previous studies have been limited to within V1, leaving much unknown about broader connectivity rules. In this study, we leverage the millimeter-scale MICrONS dataset to analyze synaptic connectivity and functional properties of individual neurons across cortical layers and areas. Our results reveal that neurons with similar responses are preferentially connected both within and across layers and areas -- including feedback connections -- suggesting the universality of the like-to-like connectivity across the visual hierarchy. Using a validated digital twin model, we separated neuronal tuning into feature (what neurons respond to) and spatial (receptive field location) components. We found that only the feature component predicts fine-scale synaptic connections, beyond what could be explained by the physical proximity of axons and dendrites. We also found a higher-order rule where postsynaptic neuron cohorts downstream of individual presynaptic cells show greater functional similarity than predicted by a pairwise like-to-like rule. Notably, recurrent neural networks (RNNs) trained on a simple classification task develop connectivity patterns mirroring both pairwise and higher-order rules, with magnitude similar to those in the MICrONS data. Lesion studies in these RNNs reveal that disrupting like-to-like connections has a significantly greater impact on performance compared to lesions of random connections. These findings suggest that these connectivity principles may play a functional role in sensory processing and learning, highlighting shared principles between biological and artificial systems.

neuroscience↗

bioRxiv2023

Pattern completion and disruption characterize contextual modulation in mouse visual cortex

Vision is fundamentally context-dependent, with neuronal responses influenced not just by local features but also by surrounding contextual information. In the visual cortex, studies using simple grating stimuli indicate that congruent stimuli--where the center and surround share the same orientation--are more inhibitory than when orientations are orthogonal, potentially serving redundancy reduction and predictive coding. Understanding these center-surround interactions in relation to natural image statistics is challenging due to the high dimensionality of the stimulus space, yet crucial for deciphering the neuronal code of real-world sensory processing. Utilizing large-scale recordings from mouse V1, we trained convolutional neural networks (CNNs) to predict and synthesize surround patterns that either optimally suppressed or enhanced responses to center stimuli, confirmed by in v ivo experiments. Contrary to the notion that congruent stimuli are suppressive, we found that surrounds that completed patterns based on natural image statistics were facilitatory, while disruptive surrounds were suppressive. Applying our CNN image synthesis method in macaque V1, we discovered that pattern completion within the near surround occurred more frequently with excitatory than with inhibitory surrounds, suggesting that our results in mice are conserved in macaques. Further, experiments and model analyses confirmed previous studies reporting the opposite effect with grating stimuli in both species. Using the MICrONS functional connectomics dataset, we observed that neurons with similar feature selectivity formed excitatory connections regardless of their receptive field overlap, aligning with the pattern completion phenomenon observed for excitatory surrounds. Finally, our empirical results emerged in a normative model of perception implementing Bayesian inference, where neuronal responses are modulated by prior knowledge of natural scene statistics. In summary, our findings identify a novel relationship between contextual information and natural scene statistics and provide evidence for a role of contextual modulation in hierarchical inference.

neuroscience↗

bioRxiv2023

Hybrid immunity elicits potent cross-variant ADCC against SARS-CoV-2 through a combination of anti-S1 and S2 antibodies

Antibodies capable of neutralising SARS-CoV-2 have been well studied, but the Fc receptor-dependent antibody activities that also significantly impact the course of infection have not been studied in such depth. SARS-CoV-2 infection induces antibody-dependent NK cell responses targeting multiple antigens, however, as most vaccines induce only anti-spike antibodies, we investigated spike-specific antibody-dependent cellular cytotoxicity (ADCC). Vaccination produced antibodies that only weakly induced ADCC, however, antibodies from individuals who were infected prior to vaccination ( hybrid immunity) elicited much stronger anti-spike ADCC. Quantitative and qualitative aspects of humoral immunity contributed to this capability, with infection skewing IgG antibody production towards S2, vaccination skewing towards S1 and hybrid immunity evoking strong responses against both domains. The capacity for hybrid immunity to provide superior spike-directed ADCC was associated with selectively increased antibody responses against epitopes within both S1 and S2. Antibodies targeting both spike domains were important for strong antibody-dependent NK cell activation, with three regions of antibody reactivity outside the receptor-binding domain (RBD) corresponding with potent anti-spike ADCC. Consequently, ADCC induced by hybrid immunity with ancestral antigen was conserved against variants containing neutralisation escape mutations in the RBD [Delta and Omicron (BA.1)]. Induction of antibodies recognizing a broad range of spike epitopes and eliciting strong and durable ADCC may partially explain why hybrid immunity provides superior protection against infection and disease than vaccination alone, and demonstrates that spike-only subunit vaccines would benefit from strategies to induce a combination of S1- and S2-specific antibody responses. SignificanceNeutralising antibodies prevent the entry of cell-free virus, however, antibodies that promote Fc-dependent activities such as ADCC are critical to control cell-associated virus. Although current SARS-CoV-2 vaccines induce potent neutralising antibodies, they fail to induce robust ADCC. Our demonstration that hybrid immunity induces superior ADCC with pan-variant activity may partially explain why hybrid immunity offers enhanced protection against reinfection. It also highlights that vaccine strategies based on expression of the spike subunit alone should not focus solely on inducing antibody responses targeting the receptor binding domain.

immunology↗

bioRxiv2023

Protein Sequence Design by Entropy-based Iterative Refinement

Inverse Protein Folding (IPF) is an important task of protein design, which aims to design sequences compatible with a given backbone structure. Despite the prosperous development of algorithms for this task, existing methods tend to leverage limited and noisy residue environment when generating sequences. In this paper, we develop an iterative sequence refinement pipeline, which can refine the sequence generated by existing sequence design models. It selects and retains reliable predictions based on the models confidence in predicted distributions, and decodes the residue type based on a partially visible environment. The proposed scheme can consistently improve the performance of a number of IPF models on several sequence design benchmarks, and increase sequence recovery of the SOTA model by up to 10%. We finally show that the proposed model can be applied to redesign Transposon-associated transposase B. 8 variants exhibit improved gene editing activity among the 20 variants we proposed. Our code and a demo of the refinement pipeline are provided in the online colab.

bioinformatics↗

bioRxiv2023

Conditional, tissue-specific CRISPR/Cas9 vector system in zebrafish reveal the role of neuropilin-1b in heart regeneration

CRISPR/Cas9 technology-mediated genome editing has significantly improved the targeted inactivation of genes in vitro and in vivo in many organisms. In this study, we have reported a novel CRISPR-based vector system for conditional tissue-specific gene ablation in zebrafish. Specifically, the cardiac-specific cardiac myosins light chain 2 (cmlc2) promoter drives Cas9 expression to silence the neuropilin-1(nrp1) gene in cardiomyocytes in a heat-shock inducible manner. This vector system establishes a unique tool to regulate the gene knockout in both the developmental and adult stages and hence, widens the possibility of loss-of-function studies in zebrafish at different stages of development and adulthood. Using this approach, we investigated the role of neuropilin isoforms nrp1a and nrp1b in response to cardiac injury and regeneration in adult zebrafish hearts. We observed that both the isoforms (nrp1a and nrp1b) are upregulated after the cryoinjury. Interestingly, the nrp1b-knockout significantly altered heart regeneration and impaired cardiac function in the adult zebrafish, demonstrated by reduced heart rate (ECG), ejection fractions, and fractional shortening. In addition, we show that the knockdown of nrp1b but not nrp1a induces activation of the cardiac remodeling genes in response to cryoinjury. To our knowledge, this is the first study where we have reported a heat shock-mediated conditional knockdown of nrp1a and nrp1b isoforms using CRISPR/Cas9 technology in the cardiomyocyte in zebrafish, and furthermore have identified a crucial role for nrp1b isoform in zebrafish cardiac remodeling and eventually heart function in response to injury.

molecular biology↗

bioRxiv2022

Targeting a broad spectrum of KRAS-mutant cancers by hyperactivation-induced cell death

The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where numerous different activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds overactive mutant forms to limit oncogenic KRAS signalling and maintain RAS- activity at an optimal level. Depletion of SHANK3 results in hyperactivation of KRAS/mitogen-activated protein kinase (MAPK) signalling, which in turn selectively induces MAPK/ERK-dependent cell death in KRAS-mutant cancers. Furthermore, targeting of this therapeutic vulnerability through nanobody- or RNA interference- mediated disruption of the SHANK3-KRAS interaction reduces tumour growth in vivo. Thus, inhibition of the SHANK3-KRAS interaction represents a new pan-KRAS-mutant compatible strategy for selective killing of KRAS- mutant cancer cells through excessive signalling. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/508660v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@87e71forg.highwire.dtl.DTLVardef@56cf94org.highwire.dtl.DTLVardef@1561136org.highwire.dtl.DTLVardef@183f711_HPS_FORMAT_FIGEXP M_FIG C_FIG Schematic model of SHANK3-controlled cell fate in KRAS-mutant cancers. SHANK3 directly interacts with KRAS and competes with RAF for KRAS binding to sustain oncogenic RAS-MAPK/ERK signalling at an optimal level (i.e. below toxic oncogenic signalling) in KRAS-mutant cancers. SHANK3 silencing (1) and inhibition of SHANK3-KRAS interaction (2) drive KRAS-mutant cells into cell death.

cancer biology↗

bioRxiv2022

Chromatin Remodeling in Patient-Derived Colorectal Cancer Models

Patient-Derived Organoids (PDO) and Xenografts (PDX) are the current gold standards for patient derived models of cancer (PDMC). Nevertheless, how patient tumor cells evolve in these models and the impact on drug response remains unclear. Herein, we compared the transcriptomic and chromatin accessibility landscapes of six matched sets of colorectal cancer (CRC) PDO, PDX, PDO-derived PDX (PDOX), and original patient tumors (PT) and discovered two major remodeling axes. The first axis delineates PDX and PDO from PT, and the second axis distinguishes PDX and PDO. PDOX were more similar to PDX than they were to PDO, indicating that the growth environment is a driving force for chromatin adaptation. Using bivariate genomic footprinting analysis, we identified transcription factors (TF) that differentially bind to open chromatins between matched PDO and PDOX. Among them, KLF14 and EGR2 footprints were enriched in all six PDOX relative to matched PDO, and silencing of KLF14 or EGR2 promoted tumor growth. Furthermore, EPHA4, a shared downstream target gene of KLF14 and EGR2, altered tumor sensitivity to MEK inhibitor treatment. Altogether, patient-derived CRC cells undergo both common and distinct chromatin remodeling in PDO and PDX/PDOX, driven largely by their respective microenvironments, which results in differences in growth and drug sensitivity and needs to be taken into consideration when interpreting their ability to predict clinical outcome.

cancer biology↗

bioRxiv2022

Global quantitative understanding of yeast's fate decision making in response to sexual deception

Cell cycle arrest and polarized cell growth are commonly used to qualitatively characterize the fate of yeast in response to pheromone. However, the quantitative decision-making process underlying the time-dependent changes in cell fate remains unclear. Here, by observing the multi-dimensional responses at the single-cell level experimentally, we find that yeast cells have various fates. Multiple states are revealed, along with the kinetic switching rates and pathways among them, giving rise to a quantitative landscape of mating response. We developed a theoretical framework using a nonequilibrium landscape and flux theory to account for the cell morphology observed experimentally and performed a stochastic simulation of biochemical reactions to explain the signal transduction and cell growth. Our experimental results established the first global quantitative demonstration of the real-time synchronization of intracellular signaling with their physiological growth and morphological functions which reveals the underlying physical mechanism. This study provides an emerging mechanistic approach for understanding the nonequilibrium global pheromone-regulated cell fate decision-making in growth and morphology.

biophysics↗

bioRxiv2022

Deciphering of Somatic Mutational Signatures of Cancer

Somatic mutational signatures (MSs) identified by genome sequencing play important roles in exploring the cause and development of cancer. Thus far, many such signatures have been identified, and some of them do imply causes of cancer. However, a major bottleneck is that we do not know the potential meanings (i.e., cancer causal or biological functions) and contributing genes for most of them. Here we presented a computational framework, Gene Somatic Genome Pattern (GSGP), which can decipher the molecular mechanisms of the MSs. More importantly, it is the first time, GSGP is able to process MSs from RNA sequencing, which greatly extended the applications of both MS analysis and RNA sequencing. As a result, GSGP analysis matches consistently with previous reports and identify the aetiologies for a number of novel signatures. Notably, we applied GSGP to RNA sequencing data and revealed an RNA-derived MS involved in deficient DNA mismatch repair (dMMR) and microsatellite instability (MSI) in colorectal cancer (CRC).

genomics↗

bioRxiv2022

Immunological memory to Common Cold Coronaviruses assessed longitudinally over a three-year period

Understanding immune memory to Common Cold Coronaviruses (CCCs) is relevant for assessing its potential impact on the outcomes of SARS-CoV-2 infection, and for the prospects of pan-corona vaccines development. We performed a longitudinal analysis, of pre-pandemic samples collected from 2016-2019. CD4+ T cells and antibody responses specific for CCC and to other respiratory viruses, and chronic or ubiquitous pathogens were assessed. CCC-specific memory CD4+ T cells were detected in most subjects, and their frequencies were comparable to those for other common antigens. Notably, responses to CCC and other antigens such as influenza and Tetanus Toxoid (TT) were sustained over time. CCC-specific CD4+ T cell responses were also associated with low numbers of HLA-DR+CD38+ cells and their magnitude did not correlate with yearly changes in the prevalence of CCC infections. Similarly, spike RBD-specific IgG responses for CCC were stable throughout the sampling period. Finally, high CD4+ T cell reactivity to CCC, but not antibody responses, was associated with high pre-existing SARS-CoV-2 immunity. Overall, these results suggest that the steady and sustained CCC responses observed in the study cohort are likely due to a relatively stable pool of CCC-specific memory CD4+ T cells instead of fast decaying responses and frequent reinfections.

immunology↗

bioRxiv2022

A Self-attention Graph Convolutional Network for Precision Multi-tumour Early Diagnostics with DNA Methylation Data

DNA methylation data-based precision tumor early diagnostics is emerging as state of the art technology, which could capture the signals of cancer occurrence 3[~]5 years in advance and clinically more homogenous groups. At present, the sensitivity of early detection for many tumors is about 30%, which needs to be significantly improved. Nevertheless, based on the genome wide DNA methylation information, one could comprehensively characterize the entire molecular genetic landscape of the tumors and subtle differences among various tumors. With the accumulation of DNA methylation data, we need to develop high-performance methods that can model and consider more unbiased information. According to the above analysis, we have designed a self-attention graph convolutional network to automatically learn key methylation sites in a data-driven way for precision multi-tumor early diagnostics. Based on the selected methylation sites, we further trained a multi-class classification support vector machine. Large amount experiments have been conducted to investigate the performance of the computational pipeline. Experimental results demonstrated the effectiveness of the selected key methylation sites which are highly relevant for blood diagnosis.

bioinformatics↗