Biology subjects

Kim, K.

Publications and source records attributed to Kim, K..

At least 217 records · Page 12Linked to original sources

bioRxiv2023

Chronic activation of the aryl hydrocarbon receptor in muscle exacerbates ischemic pathology in chronic kidney disease

Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the cellular and physiological mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic toxins, many of which are ligands for the aryl hydrocarbon receptor (AHR), are associated with adverse limb outcomes in PAD. We hypothesized that chronic AHR activation, driven by the accumulation of tryptophan-derived uremic metabolites, may mediate the myopathic condition in the presence of CKD and PAD. Both PAD patients with CKD and mice with CKD subjected to femoral artery ligation (FAL) displayed significantly higher mRNA expression of classical AHR-dependent genes (Cyp1a1, Cyp1b1, and Aldh3a1) when compared to either muscle from the PAD condition with normal renal function (P<0.05 for all three genes) or non-ischemic controls. Skeletal-muscle-specific AHR deletion in mice (AHRmKO) significantly improved limb muscle perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and contractile function, as well as enhanced mitochondrial oxidative phosphorylation and respiratory capacity in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. These findings establish chronic AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in PAD. Further, the totality of the results provide support for testing of clinical interventions that diminish AHR signaling in these conditions.

physiology↗

bioRxiv2023

CK2α-dependent regulation of Wnt activity governs white matter development and repair

Wnt signaling plays an essential role in developmental and regenerative myelination in the CNS. The Wnt signaling pathway is comprised of multiple regulatory layers; thus, how these processes are coordinated to orchestrate oligodendrocyte development remains unclear. Here we show CK2, a Wnt/{beta}-catenin signaling Ser/Thr kinase, phosphorylates Daam2, inhibiting its function and Wnt-activity during oligodendrocyte development. Intriguingly, we found Daam2 phosphorylation differentially impacts distinct stages of oligodendrocyte development, accelerating early differentiation followed by decelerating maturation and myelination. Application towards white matter injury revealed CK2-mediated Daam2 phosphorylation plays a protective role for developmental and behavioral recovery after neonatal hypoxia, while promoting myelin repair following adult demyelination. Together, our findings identify a novel regulatory node in the Wnt pathway that regulates oligodendrocyte development via protein phosphorylation-induced signaling complex instability and highlights a new biological mechanism for myelin restoration. SignificanceWnt signaling plays a vital role in OL development and has been implicated as an adverse event for myelin repair after white matter injury. Emerging studies have shed light on multi-modal roles of Wnt effectors in the OL lineage, but the underlying molecular mechanisms and modifiable targets in OL remyelination remain unclear. Using genetic mouse development and injury model systems, we delineate a novel stage-specific function of Daam2 in Wnt signaling and OL development via a S704/T7-5 phosphorylation mechanism, and determine a new role of the kinase CK2 in contributing to OL development. In-depth understanding of CK2-Daam2 pathway regulation will allow us to precisely modulate its activity in conjunction with Wnt signaling and harness its biology for white matter pathology.

neuroscience↗

bioRxiv2023

Astrocytic Slc4a4 regulates blood-brain barrier integrity in healthy and stroke brains via a NO-CCL2-CCR2 pathway

Astrocytes play vital roles in blood-brain barrier (BBB) maintenance, yet how they support BBB integrity under normal or pathological conditions remains poorly defined. Recent evidence suggests pH homeostasis is a new cellular mechanism important for BBB integrity. In the current study, we investigated the function of an astrocyte-specific pH regulator, Slc4a4, in BBB maintenance and repair. We show that astrocytic Slc4a4 is required for normal astrocyte morphological complexity and BBB function. Multi-omics analyses identified increased astrocytic secretion of CCL2 coupled with dysregulated arginine-NO metabolism after Slc4a4 deletion. Using a model of ischemic stroke, we found that loss of Slc4a4 exacerbates BBB disruption and reactive gliosis, which were both rescued by pharmacological or genetic inhibition of the NO-CCL2 pathway in vivo. Together, our study identifies the astrocytic Slc4a4-NO-CCL2 axis as a pivotal mechanism controlling BBB integrity and repair, while providing insights for a novel therapeutic approach against BBB-related CNS disorders.

neuroscience↗

bioRxiv2023

Mature microRNA-binding protein QKI promotes microRNA-mediated gene silencing

Although Argonaute (AGO) proteins have been the focus of microRNA (miRNA) studies, we observed AGO-free mature miRNAs directly interacting with RNA-binding proteins, implying the sophisticated nature of fine-tuning gene regulation by miRNAs. To investigate microRNA-binding proteins (miRBPs) globally, we analyzed PAR-CLIP data sets to identify RBP quaking (QKI) as a novel miRBP for let-7b. Potential existence of AGO-free miRNAs were further verified in genetically engineered AGO-depleted human and mouse cells. We have shown that QKI serves as an auxiliary factor empowering AGO2/let-7b-mediated gene silencing. Depletion of QKI decreases interaction of AGO2 with let-7b and target mRNA, consequently controlling target mRNA decay. QKI, however, also suppresses the dissociation of let-7b from AGO2, and slows assembly of AGO2/miRNA/target mRNA complexes at the single-molecule level. We also revealed that QKI suppresses cMYC expression at post-transcriptional level, and decreases proliferation and migration of HeLa cells, demonstrating that QKI is a tumor suppressor gene by in part augmenting let-7b activity. Our data show that QKI is a new type of RBP implicated in the versatile regulation of miRNA-mediated gene silencing.

biochemistry↗

bioRxiv2023

Antibody landscape of C57BL/6 mice cured of B78 melanoma via immunotherapy

1Antibodies can play an important role in innate and adaptive immune responses against cancer, and in preventing infectious disease. Flow cytometry analysis of sera of immune mice that were previously cured of their melanoma through a combined immunotherapy regimen with long-term memory showed strong antibody-binding against melanoma tumor cell lines. Using a high-density whole-proteome peptide array, we assessed potential protein-targets for antibodies found in immune sera. Sera from 6 of these cured mice were analyzed with this high-density, whole-proteome peptide array to determine specific antibody-binding sites and their linear peptide sequence. We identified thousands of peptides that were targeted by 2 or more of these 6 mice and exhibited strong antibody binding only by immune, not naive sera. Confirmatory studies were done to validate these results using 2 separate ELISA-based systems. To the best of our knowledge, this is the first study of the "immunome" of protein-based epitopes that are recognized by immune sera from mice cured of cancer via immunotherapy. summaryHoefges et al. utilized a whole-proteome peptide array approach to show that C57BL/6 mice develop a large repertoire of antibodies against linear peptide sequences of their melanoma after receiving a curative immunotherapy regimen consisting of radiation and an immunocytokine.

immunology↗

bioRxiv2023

Histone variant H2B.Z acetylation is necessary for maintenance of Toxoplasma gondii biological fitness

Through regulation of DNA packaging, histone proteins are fundamental to a wide array of biological processes. A variety of post-translational modifications (PTMs), including acetylation, constitute a proposed histone code that is interpreted by "reader" proteins to modulate chromatin structure. Canonical histones can be replaced with variant versions that add an additional layer of regulatory complexity. The protozoan parasite Toxoplasma gondii is unique among eukaryotes in possessing a novel variant of H2B designated H2B.Z. The combination of PTMs and the use of histone variants is important for gene regulation in T. gondii, offering new targets for drug development. In this work, T. gondii parasites were generated in which the 5 N-terminal acetylatable lysines in H2B.Z were mutated to either alanine (c-Myc-A) or arginine (c-Myc-R). c-Myc-A mutant only displayed a mild effect in its ability to kill mice. c-Myc-R mutant presented an impaired ability to grow and an increase in differentiation to latent bradyzoites. This mutant line was also more sensitive to DNA damage, displayed no virulence in mice, and provided protective immunity against future infection. While nucleosome composition was unaltered, key genes were abnormally expressed during in vitro bradyzoite differentiation. Our results show that the N-terminal positive charge patch of H2B.Z is important for these procceses. Pull down assays with acetylated N-terminal H2B.Z peptide and unacetylated one retrieved common and differential interactors. Acetylated peptide pulled down proteins associated with chromosome maintenance/segregation and cell cycle, opening the question of a possible link between H2B.Z acetylation status and mitosis.

cell biology↗

bioRxiv2023

Small Molecule Activation of NAPE-PLD Enhances Efferocytosis by Macrophages

N-acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes N-acyl-phosphatidylethanolamine (NAPEs) to form N-acyl-ethanolamides (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance, NAPEPLD expression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators (VU534 and VU533) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced in Napepld-/- BMDM or after Nape-pld inhibition. Together these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.

biochemistry↗

bioRxiv2022

A high-throughput machine vision-based univariate scale for pain and analgesia in mice

1Treatment of acute and chronic pain represent a widespread clinical challenge with poor therapeutic options. While rodents are an invaluable model to study pain, scoring nociceptive responses in clinically relevant paradigms and at high-throughput remains an unmet challenge. Therefore, there is a need for automated, high-throughput methods that sensitively and accurately assess pain and analgesia. Such objective and scalable technologies will enable the discovery of novel analgesics and yield mechanistic insights into the neural and genetic mechanisms of pain. Here, we adopt the open field arena to build a univariate scale for the formalin injection model of inflammatory pain by using a machine learning approach that incorporates 82 behavioral features. This tool outperforms traditional measures of licking and shaking in detection of formalin dose, and was validated using 4 diverse mouse strains. We also detected previously unreported differences in formalin induced nocifensive behaviors that were strain and sex specific. This model also reliably identifies morphine induced antinociception. This novel, sensitive, and inexpensive tool provides a method for quantifying voluntary nociceptive responses to facilitate genetic mapping and analgesic compound screening in a high throughput manner.

animal behavior and cognition↗

bioRxiv2022

Biosynthesis of Kratom Opioids

Mitragyna speciosa (kratom) derived monoterpenoid indole alkaloids (MIAs) such as mitragynine and 7-hydroxymitragynine are a new class of opioids with a corynanthe MIA pharmacophore that is responsible for their significantly reduced side effects and superior safety profiles. While botanical kratom has been historically used for stimulation and pain management in Southeast Asia, the biosynthesis of kratom MIAs is not known. In this study, we identified and characterized 9 reductases bearing various degrees of demethyldihydrocoryanthine/demethylcorynantheidine synthase activity and a new SABATH type methyltransferase that catalyzes highly unusual non-aromatic enol methylation from kratom and several other species, which are required in kratom opioids biosynthesis. With unnatural substrate 4-hydroxytryptamine, we further showed the biosynthesis of mitragynine and its epimer speciogynine using these characterized enzymes. The promiscuity of kratom opioid biosynthetic enzymes suggests that derivatives and analogs of kratom opioids may be manufactured in heterologous systems with appropriate enzymes and substrates.

biochemistry↗

bioRxiv2022

Hippocampal neuronal synchronization in the rat - Dissociation of perception and associative learning.

Learning requires flexible switching between perceiving and encoding external sensory stimuli, making associations with representations already stored in memory (retrieval) and acting accordingly to adapt to the environment. Hippocampus is known to be central in creating mnemonic representations, but how it could support the integration of these processes of memory encoding and retrieval during repetitive learning experiences has remained unknown. In this study, we recorded local-field potentials (LFPs) from the dorsal hippocampus during classical trace eyeblink conditioning in rats. An auditory conditioned stimulus (CS) was followed by a periorbital shock-unconditioned stimulus (US). From the LFPs, we separated hippocampal oscillations that were linked with the variation in the trial-by-trial processing of the CS from those linked with the gradual learning of the CS-US association over daily sessions of training. Short latency transient theta and gamma band oscillations were associated with learning so that both the oscillation amplitudes (strength) and phase locking increased as a function of training. In contrast, long-latency sustained alpha and beta oscillations were associated with perception of CS. These data show divergent oscillatory neural signatures for perception and learning in hippocampal subfields.

neuroscience↗

bioRxiv2022

Clonally-Expanded, Thyrotoxic Autoimmune Mediator CD8+ T cells Driven by IL21 Contribute to Checkpoint Inhibitor Thyroiditis

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) cancer therapy and is an increasing clinical challenge with the expanding use of these treatments. To date, human immunopathogenic studies of immune related adverse events (IRAEs) have relied upon sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from subjects with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates to those from subjects with spontaneous autoimmune Hashimotos thyroiditis (HT) or no thyroid disease. Single cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells ("CD8+ autoimmune mediators) present in ICI-thyroiditis, but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin 21, a cytokine secreted by intrathyroidal T follicular (Tfh) and T peripheral helper (Tph) cells, as a driver of these thyrotoxic CD8+ autoimmune mediators. In the presence of IL21, human CD8+ T cells acquired the autoimmune mediator phenotype with upregulation of cytotoxic molecules (IFN{gamma}, granzyme); the chemokine receptor CXCR6; and thyrotoxic capacity. We validated these findings in vivo using a novel mouse model of IRAEs, and further demonstrated that genetic blockade of IL21 signaling protected ICI-treated mice from thyroid immune infiltration. Taken together these studies reveal novel mechanisms and therapeutic targets by which IL21+ Tfh/Tph cells drive thyrotoxic CD8+ autoimmune mediators for the development of IRAEs in humans. One Sentence SummaryScRNAseq reveals a novel role for CD8+ autoimmune mediators and IL21+ T helper cells in the pathogenesis of human checkpoint inhibitor thyroiditis.

immunology↗

bioRxiv2022

Neurodegeneration Risk Factor, EIF2AK3 (PERK), Influences Tau Protein Aggregation

Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms - Unfolded Protein Response (UPR) and Integrated Stress Response (ISR). Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signaling in vitro. But, it remained unclear how altered PERK activity led to tauopathy. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation while inhibition exacerbated tau aggregation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. We found that tauopathy-associated PERK variants targeted the ER luminal domain; and two of these variants damaged hydrogen bond formation. Our studies support that PERK activity protects against tau aggregation and pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Finally, our studies identify small molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology.

neuroscience↗

bioRxiv2022

Low-intensity transcranial focused ultrasound changes pain-associated behaviors by modulating pain processing brain circuits

There is an urgent and unmet clinical need to develop non-pharmacological interventions for chronic pain management due to the critical side effects of opioids. Low-intensity transcranial focused ultrasound is an emerging non-invasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we developed a tightly-focused 128-element ultrasound transducer to specifically target small mouse brains, employing dynamic focus steering. We demonstrate that transcranial focused ultrasound stimulation at pain processing brain circuits can significantly alter pain-associated behaviors in mouse models in vivo. Our findings indicate that a single-session focused ultrasound stimulation to the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild-type mice and modulates heat and mechanical hyperalgesia in a humanized mouse model of chronic pain in sickle cell disease. Results further revealed a sustained behavioral change associated with heat hypersensitivity by targeting deeper cortical structures (e.g., insula) and multi-session focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitive- and chronic hyperalgesia-associated neural signals following focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting inter-experiment intervals, and investigating effects on age, gender, genotype, and in a head-fixed awake model. Importantly, transcranial focused ultrasound was shown to be safe, causing no adverse effects on motor function and brain neuropathology. In conclusion, the rich experimental evidence validates the ability of novel focused ultrasound neuromodulation to suppress pain, presenting significant translational potential for next-generation chronic pain treatment without adverse effects. Key pointsO_LINovel non-invasive neuromodulation of brains pain processing circuits with submillimeter spatial precision for pain management C_LIO_LITranscranial focused ultrasound significantly modulates pain-related behaviors and brain electrical rhythms of pain in humanized SCD mice C_LI

bioengineering↗

bioRxiv2022

Protein-coding evolution does not explain divergence in petal anthocyanin pigmentation between two monkeyflower species

Phenotypic transitions in related taxa often share a common genetic basis, which suggests that there are constraints that shape the process of evolution at the genetic level. For example, noncoding changes in a gene might be favored relative to coding changes due to being less constrained by pleiotropic effects. Here we evaluate the importance of coding-sequence changes to the recent evolution of a novel anthocyanin pigmentation trait in the monkeyflower genus Mimulus. The magenta-flowered Mimulus luteus var. variegatus recently gained petal lobe anthocyanin pigmentation via a single-locus Mendelian difference from its sister taxon, the yellow-flowered M. l. luteus. Previous work showed that the differentially expressed transcription factor gene MYB5a/NEGAN is the single causal gene. However, it was not clear whether MYB5a coding-sequence evolution (in addition to the observed patterns of differential expression) might also have contributed to increased anthocyanin production in M. l. variegatus. Quantitative image analysis of tobacco leaves, transfected with highly expressed MYB5a coding sequence from each taxon, revealed robust anthocyanin production driven by both alleles compared to a negative control. Counter to expectations, significantly higher anthocyanin production was driven by the coding sequence from the low-anthocyanin taxon M. l. luteus. Together with previously-published expression studies, this supports the hypothesis that petal pigment in M. l. variegatus was not gained by protein-coding changes, but instead via non- coding cis-regulatory evolution. Finally, while constructing the transgenes needed for this experiment, we unexpectedly discovered two sites in MYB5a that appear to be post- transcriptionally edited - a phenomenon that has been rarely reported, and even less often explored, for nuclear-encoded plant mRNAs.

molecular biology↗

bioRxiv2022

Assembly of 43 diverse human Y chromosomes reveals extensive complexity and variation

The prevalence of highly repetitive sequences within the human Y chromosome has led to its incomplete assembly and systematic omission from genomic analyses. Here, we present long-read de novo assemblies of 43 diverse Y chromosomes spanning 180,000 years of human evolution, including two from deep-rooted African Y lineages, and report remarkable complexity and diversity in chromosome size and structure, in contrast with its low level of base substitution variation. The size of the Y chromosome assemblies varies extensively from 45.2 to 84.9 Mbp and include, on average, 81 kbp of novel sequence per Y chromosome. Half of the male-specific euchromatic region is subject to large inversions with a >2-fold higher recurrence rate compared to inversions in the rest of the human genome. Ampliconic sequences associated with these inversions further show differing mutation rates that are sequence context-dependent and some ampliconic genes show evidence for concerted evolution with the acquisition and purging of lineage-specific pseudogenes. The largest heterochromatic region in the human genome, the Yq12, is composed of alternating arrays of DYZ1 and DYZ2 repeat units that show extensive variation in the number, size and distribution of these arrays, but retain a 1:1 copy number ratio of the monomer repeats, consistent with the notion that functional or evolutionary forces are acting on this chromosomal region. Finally, our data suggests that the boundary between the recombining pseudoautosomal region 1 and the non-recombining portions of the X and Y chromosomes lies 500 kbp distal to the currently established boundary. The availability of sequence-resolved Y chromosomes from multiple individuals provides a unique opportunity for identifying new associations of specific traits with Y-chromosomal variants and garnering novel insights into the evolution and function of complex regions of the human genome.

genomics↗

bioRxiv2022

Expression profiles of hypoxia-related genes of cancers originating from anatomically similar locations using TCGA database analysis

Hypoxia is a well-recognized characteristic of the tumor microenvironment of solid cancers. This study aimed to analyze hypoxia-related genes shared by groups based on tumor location. Nine hypoxia-related pathways from the Kyoto Encyclopedia of Genes and Genomes database or the Reactome database were selected, and 850 hypoxia-related genes were analyzed. Based on their anatomical locations, 14 tumor types were categorized into the following six groups. The group-specific genetic risk score was classified as high or low risk based on mRNA expression, and survival outcomes were evaluated. The risk scores in the Female reproductive group and Lung group were internally and externally validated. In the Female reproductive group, CDKN2A, FN1 and ITGA5, were identified as hub genes associated with poor prognosis, while IL2RB and LEF1 were associated with favorable prognosis. In the Lung group, ITGB1 and LDHA were associated with poor prognosis, and GLS2 was associated with favorable prognosis. Functional enrichment analysis showed that the Female reproductive group was enriched in terms related to cilia and skin, while the Lung group was enriched in terms related to cytokines and defense. This analysis may lead to better understanding of the mechanisms of cancer progression and facilitate establishing new biomarkers for prognosis prediction.

bioinformatics↗

bioRxiv2022

Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment

Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a causal factor in regeneration failure. We demonstrate that the SLRPs Chondroadherin, Fibromodulin, Lumican, and Prolargin are enriched in human, but not zebrafish, CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer structural and mechanical properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as previously unknown inhibitory ECM factors in the human CNS that impair axon regeneration by modifying tissue mechanics and structure. ONE SENTENCE SUMMARYComposition, structural organization, and mechanical properties of the injury ECM direct central nervous system regeneration.

neuroscience↗

bioRxiv2022

Mapping single-cell responses to population-level dynamics during antibiotic treatment

Treatment of sensitive bacteria with beta-lactam antibiotics often leads to two salient population-level features: a transient increase in total population biomass before a subsequent decline, and a linear correlation between growth and killing rates. However, it remains unclear how these population-level responses emerge from collective single-cell responses. During beta-lactam treatment, it is well recognized that individual cells often exhibit varying degrees of filamentation before lysis. We show that the probability of cell lysis increases with the extent of filamentation and that this dependence is characterized by unique parameters that are specific to bacterial strain, antibiotic dose, and growth condition. Modeling demonstrates how the single-cell lysis probabilities can give rise to population-level biomass dynamics, which were experimentally validated. This mapping provides insights into how the population biomass time-kill curve emerges from single cells and allows the representation of both single-and population-level responses with universal parameters.

microbiology↗