Biology subjects

Kim, S.

Publications and source records attributed to Kim, S..

At least 307 records · Page 17Linked to original sources

bioRxiv2023

Re-assessment of the subcellular localization of Bazooka/Par-3 in Drosophila: No evidence for localization to the nucleus and the neuromuscular junction

Bazooka/Par-3 (Baz) is an evolutionarily conserved scaffold protein that together with its binding partners atypical protein kinase C (aPKC) and Par-6 forms the Par complex. This protein complex functions as a master regulator for the establishment and maintenance of cell polarity in many different cell types. In the vast majority of published research papers Par complex members have been reported to localize at the cell cortex and at intercellular junctions. However, there have also been several reports claiming localization and function of Par complex members at additional subcellular sites, in particular the nucleus, the nuclear envelope and the neuromuscular junction. In this study we have re-assessed this issue for Baz in a systematic manner. We used a variety of antibodies raised in different host animals against different epitopes of Baz for confocal imaging of Drosophila tissues. We tested the specificity of these antisera by using mosaic analysis with null mutant baz alleles and tissue-specific RNAi against baz. In addition, we used a GFP-tagged gene trap line for Baz and a bacterial artificial chromosome (BAC) expressing GFP-tagged Baz under control of its endogenous promoter in a baz null mutant background to compare the subcellular localization of the respective GFP-Baz fusion proteins to the staining results with anti-Baz antisera. Together, these experiments did not provide any evidence for specific localization of Baz to the nucleus or the neuromuscular junction.

cell biology↗

bioRxiv2023

The current landscape and emerging challenges of benchmarking single-cell methods

With the rapid development of computational methods for single-cell sequencing data, benchmarking serves as a valuable resource. As the number of benchmarking studies surges, it is timely to assess the current state of the field. We conducted a systematic literature search and assessed 282 papers, including all 130 benchmark-only papers from the search and an additional 152 method development papers containing benchmarking. This collective effort provides the most comprehensive quantitative summary of the current landscape of single-cell benchmarking studies. We examine performances across nine broad categories, including often ignored aspects such as role of datasets, robustness of methods and downstream evaluation. Our analysis highlights challenges such as how to effectively combine knowledge across multiple benchmarking studies and in what ways can the community recognise the risk and prevent benchmarking fatigue. This paper highlights the importance of adopting a community-led research paradigm to tackle these challenges and establish best practice standards.

bioinformatics↗

bioRxiv2023

Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates

Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces {delta}-catenin mRNA levels in cultured human neurons. {delta}-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking {delta}-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces {delta}-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced {delta}-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was reversed by elevating {delta}-catenin expression. Prenatal VPA exposure significantly reduced synaptic AMPA receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of {delta}-catenin functions. HighlightsO_LIPrenatal exposure of valproic acid (VPA) in mice significantly reduces synaptic {delta}-catenin protein and AMPA receptor levels in the pups brains. C_LIO_LIVPA treatment significantly impairs dendritic branching in cultured cortical neurons, which is reversed by increased {delta}-catenin expression. C_LIO_LIVPA exposed pups exhibit impaired communication such as ultrasonic vocalization. C_LIO_LINeuronal activation linked to ultrasonic vocalization is absent in VPA-exposed pups. C_LIO_LIThe loss of {delta}-catenin functions underlies VPA-induced autism spectrum disorder (ASD) in early childhood. C_LI

neuroscience↗

bioRxiv2023

TSpred: a robust prediction framework for TCR-epitope interactions based on an ensemble deep learning approach using paired chain TCR sequence data

Prediction of T-cell receptor (TCR)-epitope interactions is important for many applications such as cancer immunotherapy. However, due to the scarcity of available data, it is known to be a challenging task particularly for novel epitopes. Here, we propose TSpred, a new ensemble deep learning approach for the pan-specific prediction of TCR binding specificity based on paired chain TCR data. This method combines the predictive power of CNN and the attention mechanism to capture the patterns underlying TCR-epitope interactions. In particular, we design a reciprocal attention mechanism which contributes to higher model generalizability to unseen epitopes. We perform a comprehensive evaluation of our model and observe that TSpred achieves state-of-the-art performances in both seen and unseen epitope specificity prediction tasks. Our model performs consistently well across both of the two widely used negative sampling strategies, while avoiding the potential bias associated with each strategy. Also, compared to other predictors, it is more robust to bias related to peptide imbalance in the dataset. In addition, the reciprocal attention component of our model allows for model interpretability by capturing structurally important binding regions. Results indicate that TSpred is a robust and reliable method for the task of TCR-epitope binding prediction.

bioinformatics↗

bioRxiv2023

A High-Throughput Microphysiological Liver Chip System to Model Direct and Idiosyncratic Drug-Induced Liver Injury Using Human Liver Organoids

1.ObjectiveDrug-induced liver injury (DILI) is a major failure mode in pharmaceutical development. This study aims to address the limitations of existing preclinical models by introducing a high-throughput, microfluidic liver-on-a-chip system, termed as "Curio Barrier Liver Chips," seeded with human liver organoids to enable metabolic and phenotypic morphologic characterization. MethodsCurio Barrier liver chips, fabricated in an 8x2 well configuration, were utilized to establish 3D liver organoid cultures. Human-induced pluripotent stem cells (iPSCs) were differentiated into hepatic-like organoids (HLOs), and their viability, liver-specific functions, and pharmacological responses were assessed over 28 days. ResultsThe Curiochips successfully maintained liver physiology and function, showing strong albumin secretion and cytochrome P450 (CYP) activities through 28 days. Unlike traditional models requiring millimolar drug concentrations to detect hepatotoxicity, this platform showed increased sensitivity for APAP and FIAU at micromolar concentrations. In situ differentiation of foregut spheroids to liver organoids was also achieved, further simplifying the establishment of liver chips. Furthermore, the chips demonstrated viability, function and DILI responsiveness for 28 days making this an improved model for studying idiosyncratic DILI with prolonged drug exposure and high-throughput capabilities compared to other available systems or primary human hepatocytes. ConclusionsThe Curiochips offer an advanced, miniaturized in vitro model for early-stage drug development and a sensitive, responsive and cost-effective means to detect direct hepatotoxicity. The high-throughput capability, coupled with robust functionality and pharmacological responses make it a promising tool for improving the prediction and understanding of DILI mechanisms in general and those that required prolonged drug exposure. The model also opens new avenues for research in other chronic liver diseases.

pharmacology and toxicology↗

bioRxiv2023

Design and validation of a high-throughput in vitro model of the outer Blood-Retinal Barrier (oBRB) using the Curiochips Microphysiological System

Numerous diseases, including AMD (age-related macular degeneration), arise from the blood-retinal barrier and blood vessel abnormalities in the eye; unfortunately, there is a lack of reliable in-vitro models for their systematic study. This study describes a high-throughput microphysiological system (MPS) designed to model the outer Blood-Retinal Barrier (oBRB). The MPS platform is engineered to integrate seamlessly with high-content screening technologies, utilizing a design with a single oBRB model incorporating RPE (retina pigment epithelial cells) and endothelial cell co-culture to fit within a single 96-well. Arranged in the standard 96-well plate format, the platform allows high-throughput assessment of barrier integrity through 3D confocal imaging (ZO-1 staining), Trans Epithelial Electrical Resistance (TEER), and permeability measurements. The oBRB model enables the investigation of crosstalk among different cell types in co-culture. This includes assessing changes in the barrier integrity of the Retinal Pigment Epithelium (RPE) monolayer and investigating neovascularization events resulting from endothelial cell remodeling. The platform is positioned for utility in drug discovery and development efforts targeting diseases involving oBRB damage and choroidal neovascularization, such as age-related macular degeneration (AMD).

bioengineering↗

bioRxiv2023

Alternative Polyadenylation Determines the Functional Landscape of Inverted Alu Repeats

Inverted Alu repeats (IRAlus) are abundantly found in the transcriptome, especially in introns and 3' UTRs. Yet, the biological significance of 3' UTR IRAlus remains largely unknown. Here, we find that IRAlus induce the silencing of genes involved in essential signaling pathways. We utilize J2 antibody to directly capture and map the double-stranded RNA structure of 3' UTR IRAlus in the transcriptome. Bioinformatic analysis reveals alternative polyadenylation as a major axis of IRAlus-mediated gene regulation. Notably, the expression of mouse double minute 2 (MDM2), an inhibitor of p53, is upregulated by the exclusion of IRAlus during UTR shortening, which is exploited to silence p53 during tumorigenesis. Moreover, the transcriptome-wide UTR lengthening in neural progenitor cells results in the global downregulation of genes associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis, via IRAlus inclusion. Our study establishes the functional landscape of 3' UTR IRAlus and its role in human pathophysiology.

molecular biology↗

bioRxiv2023

Double dissociation of sensorimotor interaction mediated by visual feedback during continuous de novo motor learning

While the sensorimotor cortices are central neural substrates for motor control and learning, how the interaction between their subregions with visual cortices contributes to acquiring de novo visuomotor skills is poorly understood. We designed a continuous visuomotor task in fMRI where participants learned an arbitrary visuomotor mapping. To dissociate motor and somatosensory cortices functions, we manipulated visual feedback of a cursor such that they learned to control using fingers under two alternating conditions: online cursor feedback is available or unavailable except when a target is reached. We found double dissociation of fMRI activity in subregions of the sensorimotor and visual cortices and their interaction, which were mediated by the visual feedback. We also found a significant reduction in functional connectivity between somatosensory cortices and early visual cortices, which was highly correlated with performance improvement. These findings support the distinct interaction between subregions of sensorimotor cortices and visual cortices while highlighting the more dominant role of somatosensory cortices over motor cortices during de novo motor learning.

neuroscience↗

bioRxiv2023

Increased spatial coupling of integrin and collagen IV in the immunoresistant clear cell renal cell carcinoma tumor microenvironment

BackgroundImmunotherapy (IO) has improved survival for patients with advanced clear cell renal cell carcinoma (ccRCC), but resistance to therapy develops in most patients. We use cellular-resolution spatial transcriptomics in patients with IO naive and IO exposed primary ccRCC tumors to better understand IO resistance. Spatial molecular imaging (SMI) was obtained for tumor and adjacent stroma samples. Spatial gene set enrichment analysis (GSEA) and autocorrelation (coupling with high expression) of ligand-receptor transcript pairs were assessed. Multiplex immunofluorescence (mIF) validation was used for significant autocorrelative findings and the cancer genome atlas (TCGA) and the clinical proteomic tumor analysis consortium (CPTAC) databases were queried to assess bulk RNA expression and proteomic correlates. Results21 patient samples underwent SMI. Viable tumors following IO harbored more stromal CD8+ T cells and neutrophils than IO naive tumors. YES1 was significantly upregulated in IO exposed tumor cells. The epithelial-mesenchymal transition pathway was enriched on spatial GSEA and the associated transcript pair COL4A1-ITGAV had significantly higher autocorrelation in the stroma. Fibroblasts, tumor cells, and endothelium had the relative highest expression. More integrin V+ cells were seen in IO exposed stroma on mIF validation. Compared to other cancers in TCGA, ccRCC tumors have the highest expression of both COL4A1 and ITGAV. In CPTAC, collagen IV protein was more abundant in advanced stages of disease. ConclusionsOn spatial transcriptomics, COL4A1 and ITGAV were more autocorrelated in IO-exposed stroma compared to IO-naive tumors, with high expression amongst fibroblasts, tumor cells, and endothelium. Integrin represents a potential therapeutic target in IO treated ccRCC.

cancer biology↗

bioRxiv2023

Methyl-TWAS: A powerful method for in silico transcriptome-wide association studies (TWAS) using long-range DNA methylation

In silico transcriptome-wide association studies (TWAS) are commonly used to test whether expression of specific genes is linked to a complex trait. However, genotype-based in silico TWAS such as PrediXcan, exhibit low prediction accuracy for a majority of genes because genotypic data lack tissue- and disease-specificity and are not affected by the environment. Because methylation is tissue-specific and, like gene expression, can be modified by environment or disease status, methylation should predict gene expression with more accuracy than SNPs. Therefore, we propose Methyl-TWAS, the first approach that utilizes long-range methylation markers to impute gene expression for in silico TWAS through penalized regression. Methyl-TWAS 1) predicts epigenetically regulated/associated expression (eGReX), which incorporates tissue-specific expression and both genetically- (GReX) and environmentally-regulated expression to identify differentially expressed genes (DEGs) that could not be identified by genotype-based methods; and 2) incorporates both cis- and trans- CpGs, including various regulatory regions to identify DEGs that would be missed using cis-methylation only. Methyl-TWAS outperforms PrediXcan and two other methods in imputing gene expression in the nasal epithelium, particularly for immunity-related genes and DEGs in atopic asthma. Methyl-TWAS identified 3,681 (85.2%) of the 4,316 DEGs identified in a previous TWAS of atopic asthma using measured expression, while PrediXcan could not identify any gene. Methyl-TWAS also outperforms PrediXcan for expression imputation as well as in silico TWAS in white blood cells. Methyl-TWAS is a valuable tool for in silico TWAS, leveraging a growing body of publicly available genome-wide DNA methylation data for a variety of human tissues.

bioinformatics↗

bioRxiv2023

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes

Progressive supranuclear palsy (PSP) is a rare Parkinsonian disorder characterized by problems with movement, balance, cognition, and other symptoms. PSP differs from Alzheimers disease (AD) and other neurodegenerative diseases displaying abnormal forms of the microtubule-associated protein tau ("tauopathies") by the presence of pathology not only in neurons, but also in astrocytes and oligodendrocytes. Genetic contributors may mediate these differences, however much of PSP genetics remains unexplained. Here we conducted the largest genome-wide association study (GWAS) of PSP to date including 2,779 cases (2,595 neuropathologically-confirmed) and 5,584 controls and identified six independent PSP susceptibility loci with genome-wide significant (p < 5x10-8) associations including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations revealed a unique oligodendrocytic signature that distinguishes PSP from AD and Parkinsons disease. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identified oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, as well as an association with elevated C4A expression in bulk brain tissue which may be driven by increased C4A copy number in PSP cases. Finally, histological studies demonstrated abnormal tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies including epigenomic and eQTL analyses, we identified potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in the pathogenesis of PSP.

neuroscience↗

bioRxiv2023

Optical segmentation-based compressed readout of neuronal voltage dynamics

Functional imaging of biological dynamics generally begins with acquiring time-series images, followed by quantifying spatially averaged intensity traces for the regions of interest (ROIs). The conventional pipeline discards a substantial portion of the acquired data when quantifying intensity traces, indicative of inefficient data acquisition. Here we propose a conceptually novel acquisition pipeline that assigns each ROI to a single pixel in the detector, enabling optimally compressed acquisition of the intensity traces. As a proof-of-principle, we implemented a detection module composed of a pair of spatial light modulators and a microlens array, which segments the original image into multiple subimages by introducing distinct angular shifts to each ROI. Each subimage exclusively encodes the signal for the corresponding ROI, facilitating the compressed readout of its intensity trace using a single pixel. This spatial compression allowed for maximizing the temporal information without compromising the spatial information on ROIs. Harnessing our novel approach, we demonstrate the recording of circuit-scale neuronal voltage dynamics at over 5 kHz sampling rate, revealing the individual action potential waveforms within subcellular structures, as well as their submillisecond-scale temporal delays.

neuroscience↗

bioRxiv2023

Coordinated immune dysregulation in Juvenile Dermatomyositis revealed by single-cell genomics

Juvenile Dermatomyositis (JDM) is one of several childhood-onset autoimmune disorders characterized by a type I interferon response and autoantibodies. Treatment options are limited due to incomplete understanding of how the disease emerges from dysregulated cell states across the immune system. We therefore investigated the blood of JDM patients at different stages of disease activity using single-cell transcriptomics paired with surface protein expression. By immunophenotyping peripheral blood mononuclear cells, we observed skewing of the B cell compartment towards an immature naive state as a hallmark of JDM. Furthermore, we find that these changes in B cells are paralleled by signatures of Th2-mediated inflammation. Additionally, our work identified SIGLEC-1 expression in monocytes as a composite measure of heterogeneous type I interferon activity in disease. We applied network analysis to reveal that hyperactivation of the type I interferon response in all immune populations is coordinated with dysfunctional protein processing and regulation of cell death programming. This analysis separated the ubiquitously expressed type I interferon response into a central hub and revealed previously masked cell states. Together, these findings reveal the coordinated immune dysregulation underpinning JDM and provide novel insight into strategies for restoring balance in immune function.

immunology↗

bioRxiv2023

Chemical inhibition of stomatal differentiation by perturbation of the master-regulatory bHLH heterodimer via an ACT-Like domain

Selective perturbation of protein interactions with chemical compounds enables dissection and control of developmental processes. Differentiation of stomata, cellular valves vital for plant growth and survival, is specified by the basic-helix-loop-helix (bHLH) heterodimers. Harnessing a new amination reaction, we here report a synthesis, derivatization, target identification, and mode of action of an atypical doubly-sulfonylated imidazolone, Stomidazolone, which triggers stomatal stem cell arrest. Our forward chemical genetics followed by biophysical analyses elucidated that Stomidazolone directly binds to the C-terminal ACT-Like (ACTL) domain of MUTE, a master regulator of stomatal differentiation, and perturbs its heterodimerization with a partner bHLH, SCREAM in vitro and in plant cells. On the other hand, Stomidazolone analogs that are biologically inactive did not bind to MUTE or disrupt the SCREAM-MUTE heterodimers. Guided by structural docking modeling, we rationally designed MUTE with reduced Stomidazolone binding. These engineered MUTE proteins are fully functional and confer Stomidazolone resistance in vivo. Our study identifies doubly-sulfonylated imidazolone as a direct inhibitor of the stomatal master regulator, further expanding the chemical space for perturbing bHLH-ACTL proteins to manipulate plant development.

plant biology↗

bioRxiv2023

Medial temporal lobe functional network architecture supports sleep-related emotional memory processing in older adults

Memory consolidation occurs via reactivation of a hippocampal index during non-rapid eye movement slow-wave sleep (NREM SWS) which binds attributes of an experience existing within cortical modules. For memories containing emotional content, hippocampal-amygdala dynamics facilitate consolidation over a sleep bout. This study tested if modularity and centrality--graph theoretical measures that index the level of segregation/integration in a system and the relative import of its nodes--map onto central tenets of memory consolidation theory and sleep-related processing. Findings indicate that greater network integration is tied to overnight emotional memory retention via NREM SWS expression. Greater hippocampal and amygdala influence over network organization supports emotional memory retention, and hippocampal or amygdala control over information flow are differentially associated with distinct stages of memory processing. These centrality measures are also tied to the local expression and coupling of key sleep oscillations tied to sleep-dependent memory consolidation. These findings suggest that measures of intrinsic network connectivity may predict the capacity of brain functional networks to acquire, consolidate, and retrieve emotional memories.

neuroscience↗

bioRxiv2023

Multi-modal skin atlas associates a multicellular immune-stromal community with altered cornification and T cell expansion in atopic dermatitis

In healthy skin, a cutaneous immune system maintains the balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents. In atopic dermatitis (AD), barrier and immune dysfunction result in chronic tissue inflammation. Our understanding of the skin tissue ecosystem in AD remains incomplete with regard to the hallmarks of pathological barrier formation, and cellular state and clonal composition of disease-promoting cells. Here, we generated a multi-modal cell census of 310,691 cells spanning 86 cell subsets from whole skin tissue of 19 adult individuals, including non-lesional and lesional skin from 11 AD patients, and integrated it with 396,321 cells from four studies into a comprehensive human skin cell atlas in health and disease. Reconstruction of human keratinocyte differentiation from basal to cornified layers revealed a disrupted cornification trajectory in AD. This disrupted epithelial differentiation was associated with signals from a unique immune and stromal multicellular community comprised of MMP12+ dendritic cells (DCs), mature migratory DCs, cycling ILCs, NK cells, inflammatory CCL19+ IL4I1+ fibroblasts, and clonally expanded IL13+IL22+IL26+ T cells with overlapping type 2 and type 17 characteristics. Cell subsets within this immune and stromal multicellular community were connected by multiple inter-cellular positive feedback loops predicted to impact community assembly and maintenance. AD GWAS gene expression was enriched both in disrupted cornified keratinocytes and in cell subsets from the lesional immune and stromal multicellular community including IL13+IL22+IL26+ T cells and ILCs, suggesting that epithelial or immune dysfunction in the context of the observed cellular communication network can initiate and then converge towards AD. Our work highlights specific, disease-associated cell subsets and interactions as potential targets in progression and resolution of chronic inflammation.

molecular biology↗

bioRxiv2023

Ornaments for Accurate and Efficient Allele-Specific Expression Estimation with Bias Correction

Allele-specific expression has been used to elucidate various biological mechanisms, such as genomic imprinting and gene expression variation caused by genetic changes in cis-regulatory elements. However, existing methods for obtaining allele-specific expression from RNA-seq reads do not adequately and efficiently remove various biases, such as reference bias, where reads containing the alternative allele do not map to the reference transcriptome, or ambiguous mapping bias, where reads containing the reference allele map differently from reads containing the alternative allele. We present Ornaments, a computational tool for rapid and accurate estimation of allele-specific expression at unphased heterozygous loci from RNA-seq reads while correcting for allele-specific read mapping bias. Ornaments removes reference bias by accounting for personalized transcriptome, and ambiguous mapping bias by probabilistically assigning reads to multiple transcripts and variant loci they map to. Ornaments is a lightweight extension of kallisto, a popular tool for fast RNA-seq quantification, that improves the efficiency and accuracy of WASP, a popular tool for bias correction in allele-specific read mapping. Our experiments on simulated and human lymphoblastoid cell-line RNA-seq reads with the genomes of the 1000 Genomes Project show that Ornaments is as efficient as kallisto, an order of magnitude faster than WASP, and more accurate than WASP and kallisto. In addition, Ornaments detected genes that are imprinted at transcript level with higher sensitivity, compared to WASP that detected the imprinted signals only at gene level.

genetics↗

bioRxiv2023

Co-transcriptional translation amplifies mRNA noise in Escherichia coli

The variability in mRNA expression among isogenic cells exposed to identical environments is inherent. This variability originates from the inherent stochasticity of all processes underlying transcription. Although transcription and translation can occur simultaneously on the same mRNA molecule in bacteria, it is not well understood whether and how co-transcriptional translation contributes to variability in mRNA expression. Here, we studied the contribution of co-transcriptional translation to mRNA noise in E. coli cells. Using a transcription system physically decoupled from translation, we investigated the effect of ribosome binding to mRNA transcripts on variability in mRNA expression. We found that the propagation of RNAP noise to the mRNA level was increased by ribosome binding, leading to larger variations in the mRNA levels. We further demonstrated that ribosome binding increased the transcription initiation rate, resulting in the promoter becoming susceptible to RNAP noise. Co-transcriptional translation amplified transcriptional noise and modulated transcriptional bursting kinetics in bacterial cells.

biophysics↗