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Biology subjects

Mueller, J. L.

Publications and source records attributed to Mueller, J. L..

At least 19 recordsLinked to original sources

Hybrid Drosophila genomes rapidly purge minority ancestry but repeatedly retain selected regions

Hybridization is increasingly recognized as a widespread evolutionary process across animals, plants, and fungi, and plays a key role in driving speciation, shaping genetic diversity, and facilitating adaptation. Initial hybrid genomes are rarely observed empirically, making it challenging to observe in real time how competing forces like purifying selection and adaptive introgression interact to shape post-hybridization genomes. Here, we use replicated experimental hybrid populations between Drosophila simulans and D. sechellia to track directly genome-wide evolutionary dynamics across approximately 45 generations post-hybridization. We show that hybrid populations with primarily D. simulans ancestry rapidly recover wild-type levels of fertility and fecundity, whereas populations carrying predominantly D. sechellia ancestry experience persistent fitness reductions and frequent extinction. Genome-wide ancestry trajectories show pervasive purifying selection against minority-ancestry alleles, leading to rapid regression toward majority ancestry across the genome, with stronger purging on the X chromosome than autosomes. Following the initial purging, neutral minority ancestry stabilized at low frequencies across the genome. In striking contrast, we observe repeated increases in D. sechellia ancestry on chromosome 4 and multiple regions on chromosome 3R within D. simulans-majority populations, providing evidence for adaptive introgression. High-density sequencing revealed that these regions were repeatedly retained across independently evolving populations despite near-complete genome-wide purging. Simulations support a model in which recombination rapidly uncouples beneficial introgressed alleles from linked incompatibility-associated alleles during the initial generations, allowing positive selection to act. Our temporal allele-frequency analyses suggest that hybrid genome stabilization of the introgressed regions is highly repeatable but not identical, yielding parallel outcomes across replicate populations. We establish a tractable experimental framework to directly observe how hybrid genomes reorganize in real time, and demonstrate how purifying selection, positive selection, recombination, and stochastic processes interact to restructure hybrid genomes shortly after admixture.

genetics↗

Virus-like antigen display delivers a stand-alone danger signal through the BCR that circumvents tolerance

How B cells discriminate self from foreign antigens remains a central question, given inherent autoreactivity of the mature B cell receptor (BCR) repertoire. Soluble antigen (sAg) induces tolerance, whereas patterned antigen display on virus-like particles (pAg) triggers robust B cell responses that can proceed without T cell help. Here, we show how this divergence arises early in BCR signaling. Unlike sAg, pAg can bypass a Lyn-dependent negative feedback loop to trigger digital signaling, such that ultra-low concentrations of pAg produce strong and sustained Ca2+ responses. Surprisingly, pAg drives maximal nuclear NF-{kappa}B but limited NFAT, whereas sAg does the opposite, reflecting differential production of diacylglycerol. Consequently, sAg induced an NFAT-dependent anergy program, whereas pAg evaded this state and instead engaged a cMyc-driven program that partially resembles a TLR-dependent danger response. Our findings reveal how proximal signaling directs distinct transcriptional fate to enable immunogenic B cell responses to virus-like antigen display.

immunology↗

Acquisition of ampliconic sequences marks a selfish mouse t-haplotype

Mendelian genetics posits equal transmission of alleles, but selfish alleles can bias the transmission of large genomic regions or entire chromosomes1-4. One long-standing question is how transmission bias evolves to encompass large genomic regions. Mus musculus (house mouse) t-haplotypes exhibit up to 99% transmission bias from heterozygous males5-14 and harbor selfish alleles9-14 genetically linked to large inversions spanning the proximal half of chromosome 1715-20. Here, by generating a high-quality, single-haplotype assembly of a t- haplotype, we reveal the evolution of eight large amplicons with known11,13,21 and candidate selfish alleles as a distinct genetic feature. Three amplicons are conserved in closely related Mus species, and two have known selfish alleles in the oldest inversion, implicating amplicons and an inversion drove the origins of a selfish chromosome 17 [~]3MYA. The remaining t- haplotype amplicons harbor gene families expressed predominantly in haploid spermatids, newly acquired retrogenes, and the most differentially expressed genes in wild-type/t-haplotype spermatids. Targeted deletion of a [~]1.8Mb amplicon with candidate selfish alleles on the t- haplotype reduces selfish transmission in heterozygous males by 3%. Notably, the evolution of selfish allele-containing amplicons and inversions on the t-haplotype parallels mammalian sex chromosome evolution as signatures of selfish transmission. We propose amplicon acquisition and large inversions initiate evolutionary arms races between selfish haplotypes and serve as genome-wide signatures of selfish transmission.

genetics↗

Reenacting a mouse genetic evolutionary arms race in yeast reveals SLXL1/SLX compete with SLY1/2 for binding to Spindlins.

The house mouse X and Y chromosomes have recently acquired high copy number, rapidly evolving gene families representing an evolutionary arms race. This arms race between proteins encoded by X-linked Slxl1/Slx and Y-linked Sly gene families can distort male offspring sex ratio, but how these proteins compete remains unknown. Here, we report how Slxl1/Slx and Sly encoded proteins compete in a protein family-specific and dose-dependent manner using yeast. Specifically, SLXL1 competes with SLY1 and SLY2 for binding to the Spindlin SPIN1. Similarly, SLX competes with SLY2 for binding the Spindlin SSTY2. These competitions are driven by the N-termini of SLXL1, SLX, SLY1, and SLY2 binding to the third Tudor domains of SPIN1 and SSTY2. SLY1 and SLY2 form homo- and heterodimers, suggesting the competition is between complex multimers. Residues under positive selection mapping to the interaction domains and rapid exon gain/loss are consistent with competition between the X- and Y-linked gene families. Our findings support a model in which dose-dependent competition of these X- and Y-linked encoded proteins to bind Spindlins occurs in haploid X- and Y-spermatids to influence X-versus Y-sperm fitness and thus sex ratio. Significance StatementIn house mouse, an evolutionary arms race between proteins encoded by the X-linked Slxl1/Slx and Y-linked Sly gene families during spermatogenesis can distort male offspring sex ratio, but how these proteins compete remains unknown. We report how SLXL1/SLX competes with SLY1/SLY2 by demonstrating their dose-dependent competitive binding to Spindlins, the key protein domains and rapidly evolving residues and exons that drive the competition, and how the competition is likely between complex multimers. Our findings have broad implications for the mechanics of evolutionary arms and how competition between sex chromosomes influences X-versus Y-sperm fitness and sex ratio.

genetics↗

Non-Human Recognition of Orthography: How is it implemented and how does it differ from Human orthographic processing

The ability to robustly recognize strings of letters, a cornerstone of reading, was observed in baboons and pigeons despite their lack of phonological and semantic knowledge. Here, we apply a comparative modeling approach to investigate the neuro-cognitive basis of orthographic decision behavior in humans, baboons, and pigeons, addressing whether phylogenetic relatedness entails similar underlying neuro-cognitive phenotypes. We use the highly transparent SpeechLess Reader (SLR) model, which assumes letter-string recognition based on a computational implementation of predictive coding, whereby orthographic decisions rely on prediction-error signals emerging from multiple representational levels: visual-pixel, letter, and letter-sequence representations. We investigate which representations species use during successful orthographic decision-making. We introduce multiple SLR variants, each including one or more prediction-error representations, and compare the simulations of each variant with orthographic decisions from individuals of three species after learning letter strings without meaning. Humans predominantly relied on letter-sequence-level representations, resulting in the highest task performance in behavior and model simulations. Baboons also relied on sequence-based representations, but in combination with pixel- and letter-level representations. In contrast, pigeons relied more on pixel and letter-level representations. These findings suggest that the orthographic representations used in orthographic decisions reflect phylogenetic distance: Humans and baboons use more similar representations than pigeons. Overall, the description of orthographic decisions based on a small set of representations and computations was highly successful in describing behavior, even for humans who mastered reading in its entirety.

animal behavior and cognition↗

Transcriptional control of central T cell tolerance by NR4A family nuclear receptors

Although deletion of self-reactive thymocytes and their diversion into regulatory T cell (Treg) lineage are critical for immune tolerance and homeostasis, the molecular pathways that link antigen recognition to these fates are incompletely understood. The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to TCR signaling in the thymus and are implicated in both deletion and diversion, but the mechanisms by which they operate are not clear. Redundancy among the family members and their requirement for Treg generation and maintenance have obscured their role in negative selection. Here we take advantage of competitive bone marrow chimeras and the OT-II/RIPmOVA model to demonstrate that Nr4a1 and Nr4a3 are essential for upregulation of Bcl2l11/BIM and negative selection by tissue-restricted model self-antigen (TRA). Moreover, we reveal that the Nr4a family is absolutely required for full induction of a broad transcriptional program triggered in self-reactive thymocytes by TRA recognition, and conserved across model systems and the natural repertoire. Importantly, both model self antigen-specific TCR Tg and polyclonal thymocytes lacking Nr4a1/3 that escape negative selection acquire an anergy-like program that persists in the periphery and is also evident among wild-type recent thymic emigrants (RTEs). We propose that the Nr4a family transduces TCR signals during thymic development to enforce the fates of highly self-reactive clones, mediating not only deletion and Treg diversion, but also contributing to a cell-intrinsic, persistent anergy-like program that may operate at the margins of canonical thymic tolerance mechanisms to restrain self-reactive T cells after thymic egress.

immunology↗

Functional reorganization of brain regions supporting non-adjacent dependency learning across the first half year of life

Pre-babbling infants can track nonadjacent dependencies (NADs) in the auditory domain. While this forms a crucial prerequisite for language acquisition, the neurodevelopmental origins of this ability remain unknown. We applied functional near- infrared spectroscopy in neonates and 6-7-month-old infants to investigate the neural substrate supporting NAD learning using tone sequences in an artificial grammar learning paradigm. Detection of NADs was indicated by left prefrontal activation in neonates while by left supramarginal gyrus (SMG), superior temporal gyrus (STG), and inferior frontal gyrus activation in 6-7-month-olds. Functional connectivity analyses further indicated that the neonate activation pattern during the test phase benefited from a brain network consisting of prefrontal regions, left SMG and STG during the rest and learning phases. These findings suggest a left-hemispheric learning-related functional brain network may emerge at birth and be strengthened by complex auditory input across the first half year of life, providing a neural basis for language acquisition.

neuroscience↗

Development of a 3D in vitro human-sized model of cervical dysplasia to evaluate the delivery of ethyl cellulose-ethanol injection for the treatment of cervical dysplasia ablation

Cervical cancer, the second leading cause of cancer-related death for women worldwide, remains a preventable yet persistent disease that disproportionately affects women in low and middle-income countries (LMICs). While existing therapies for treating cervical dysplasia are effective, they are often inaccessible in LMICs. Ethanol ablation is an alternative low-cost, accessible therapy that we previously enhanced into an ethyl cellulose (EC)-ethanol gel formulation to improve efficacy. When seeking to evaluate EC-ethanol for cervical dysplasia, we found a paucity of relevant animal models. Thus, in this study, we developed a 3D in vitro model of cervical dysplasia featuring a central lesion of cervical cancer cells surrounded by fibroblasts and keratinocytes to enable the evaluation of EC-ethanol and other novel therapeutics. Our GelMA-based 3D model successfully captured the architectural complexity of cervical dysplasia, showcasing cell response and high viability. The GelMA hydrogel formulation (8.7% w/v) exhibited viscoelastic properties akin to human cervical tissue. Using micro-CT imaging, we assessed EC-ethanol injection deposition in the hydrogel, revealing retention of virtually the entire injected volume near the injection site. Finally, we evaluated the EC-ethanol injections efficacy in eliminating cervical cancer cells. The EC-ethanol injection led to a significant decrease in cancer cell viability while preserving healthy cells in the 3D in vitro model. Taken together, our in vitro model mirrored the architecture of cervical dysplasia and demonstrated the potential of EC-ethanol for localized treatment of cervical dysplasia.

bioengineering↗

An integrated signaling threshold initiates IgG response towards virus-like immunogens

Class-switched neutralizing antibody (nAb) production is rapidly induced upon many viral infections. However, due to the presence of multiple components in typical virions, the precise biochemical and biophysical signals from viral infections that initiate nAb responses remain inadequately defined. Using a reductionist system of synthetic virus-like structures (SVLS) containing minimal, highly purified biochemical components commonly found in enveloped viruses, here we show that a foreign protein on a virion-sized liposome can serve as a stand-alone danger signal to initiate class-switched nAb responses in the absence of cognate T cell help or Toll-like receptor signaling but requires CD19, the antigen (Ag) coreceptor on B cells. Introduction of internal nucleic acids (iNAs) obviates the need for CD19, lowers the epitope density (ED) required to elicit the Ab response and transforms these structures into highly potent immunogens that rival conventional virus-like particles in their ability to elicit strong Ag-specific IgG. As early as day 5 after immunization, structures harbouring iNAs and decorated with just a few molecules of surface Ag at doses as low as 100 ng induced all IgG subclasses of Ab known in mice and reproduced the IgG2a/2c restriction that has been long observed in live viral infections. These findings reveal a shared mechanism for nAb response upon viral infection. High ED is capable but not necessary for driving Ab secretion in vivo. Instead, even a few molecules of surface Ag, when combined with nucleic acids within these structures, can trigger strong antiviral IgG production. As a result, the signaling threshold for the induction of neutralizing IgG is set by dual signals originating from both ED on the surface and the presence of iNAs within viral particulate immunogens. One-sentence summaryReconstitution of minimal viral signals necessary to initiate antiviral IgG

immunology↗

Auditory associative word learning in adults: the effects of musical experience and stimulus ordering

Evidence for sequential associative word learning in the auditory domain has been identified in infants, but adults have proven to have difficulties in this type of word learning. To investigate the role of auditory expertise and auditory stimuli salience in the association of auditory objects and their labels, we tested in the first experiment auditorily-trained musicians versus athletes as a high-level control group and in the second experiment stimulus ordering, contrasting object-label versus label-object presentation. Learning was evaluated from electrophysiological (EEG) recordings during training and subsequent testing phases, as well as accuracy-judgement responses during test. Results revealed for musicians a late positive component in the EEG during testing, neither N400 nor behavioral effects were found at test, while athletes did not show any effect of learning. Moreover, the object-label-ordering group only exhibited emerging association effects during training, while the label-object-ordering group showed an EEG effect during test as well as above chance accuracy-judgement scores. Thus, our results suggest an advantage of musical expertise and more salient label-object-ordering in auditory associative word learning in adults. Implications with respect to developmental differences in auditory word learning are discussed.

neuroscience↗

Molecular basis for potent B cell responses to antigen displayed on particles of viral size

Although it has long been appreciated that multivalent antigens - and particularly viral epitope display - produce extremely rapid, robust, and T-independent humoral immune responses, the biochemical basis for such potency has been incompletely understood. Here we take advantage of a set of neutral liposomes of viral size that are engineered to display affinity mutants of the model antigen (Ag) hen egg lysozyme at precisely varied density. We show that particulate Ag display by liposomes induces highly potent B cell responses that are dose-and density-dependent but affinity-independent. Titrating dose of particulate, but not soluble, Ag reveals bimodal Erk phosphorylation and cytosolic calcium increases. Particulate Ag induces signal amplification downstream of the B cell receptor (BCR) by selectively evading LYN-dependent inhibitory pathways, but in vitro potency is independent of CD19. Importantly, Ag display on viral-sized particles signals independently of MYD88 and IRAK1/4, but activates NF-{kappa}B robustly in a manner that mimics T cell help. Together, such biased signaling by particulate Ag promotes MYC expression and reduces the threshold required for B cell proliferation relative to soluble Ag. These findings uncover a molecular basis for highly sensitive B cell response to viral Ag display and remarkable potency of virus-like particle vaccines that is not merely accounted for by avidity and BCR cross-linking, and is independent of the contribution of B cell nucleic acid-sensing machinery.

immunology↗

Differentiated neuroblastoma cells remain epigenetically poised for de-differentiation to an immature state

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for a significant share of childhood cancer deaths. Prior studies utilizing RNA sequencing of bulk tumor populations showed two predominant cell states characterized by high and low expression of neuronal genes. Although cells respond to treatment by altering their gene expression, it is unclear whether this reflects shifting balances of distinct subpopulations or plasticity of individual cells. Using neuroblastoma cell lines lacking MYCN amplification, we show that the antigen CD49b distinguishes these subpopulations. CD49b expression marks proliferative cells with an immature gene expression program, while CD49b-negative cells express differentiated neuronal marker genes and are quiescent. Sorted populations spontaneously switch between CD49b expression states in culture, and CD49b-negative cells can generate rapidly growing, CD49b-positive tumors in mice. We profiled H3K27ac to identify enhancers and super enhancers that are specifically active in each population and find that CD49b-negative cells maintain the priming H3K4me1 mark at elements that are active in CD49b-high cells. Improper maintenance of primed enhancer elements thus may underlie cellular plasticity in neuroblastoma, representing potential therapeutic targets for this lethal tumor. Summary StatementThis study demonstrates that neuroblastoma cells can interconvert between a state characterized by expression of neuronal genes and a de-differentiated state.

cancer biology↗

X-linked palindromic gene families 4930567H17Rik and Mageb5 are dispensable for male mouse fertility

Mammalian sex chromosomes are enriched for large, nearly-identical, palindromic sequences harboring genes expressed predominately in testicular germ cells. Discerning if individual palindrome-associated gene families are essential for male reproduction is difficult due to challenges in disrupting all copies within a gene family. Here we generate precise, independent, deletions to assess the reproductive roles of two X-linked palindromic gene families with spermatid-predominant expression, 4930567H17Rik or Mageb5. Via sequence comparisons, we find mouse 4930567H17Rik and Mageb5 have human orthologs, 4930567H17Rik is rapidly diverging in rodents and primates, and 4930567H17Rik is harbored in a palindrome in humans and mice, while Mageb5 is not. Mice lacking either 4930567H17Rik or Mageb5 gene families do not have detectable defects in male fertility, fecundity, spermatogenesis, or in gene regulation, but do show differences in sperm head morphology, suggesting a potential role in sperm function. We conclude that while all palindrome-associated gene families are not essential for male fertility, large palindromes influence the evolution of their associated gene families. Summary sentenceMice lacking X-palindromic gene families display normal male fertility, fecundity, spermatogenesis, and gene expression but exhibit differences in sperm head morphology, suggesting a potential role for these gene families in sperm development.

genetics↗

Regulation of layered T cell tolerance mechanisms by the NR4A family is essential to preserve immune homeostasis and suppress autoimmunity

The NR4A family of orphan nuclear receptors (Nr4a1-3) plays redundant roles upstream of Foxp3 to establish and maintain Treg identity; deletion of multiple family members in the thymus results in Treg deficiency and a severe inflammatory disease. Consequently, it has been challenging to isolate the functions of this family in other immune cells. Here we take advantage of a competitive bone marrow chimera strategy, coupled with conditional genetic tools, to rescue Treg homeostasis and unmask such functions. Unexpectedly, chimeras harboring Nr4a1-/- Nr4a3-/- (DKO) bone marrow develop autoantibodies and a systemic inflammatory disease despite a replete Treg compartment of largely wild-type origin. This disease differs qualitatively from that seen with Treg-deficiency and is B cell-extrinsic. Negative selection of DKO thymocytes is profoundly impaired in a cell-intrinsic manner. Consistent with escape of self-reactive T cells into the periphery, DKO T cells with functional and phenotypic features of anergy accumulate in chimeric mice. Despite this, DKO T cells exhibit enhanced IL-2 production, implying a cell-intrinsic role for the NR4A family in peripheral T cell tolerance. These studies reveal roles for the NR4A family in multiple layered T cell tolerance mechanisms and demonstrate that each is essential to preserve immune homeostasis.

immunology↗

Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses

B cell clones compete for entry into and dominance within germinal centers (GC), where the highest affinity BCRs are selected. However, diverse and low affinity B cells can enter and reside in GCs for extended periods. To reconcile these observations, we hypothesized that a negative feedback loop may operate within B cells to preferentially restrain high affinity clones from monopolizing the early GC niche. Here we report a role for the nuclear receptor NUR77/Nr4a1 in this process. We previously showed that NUR77 expression scales with antigen stimulation and restrains B cell expansion when T cell help is limiting. Here we show that, although NUR77 is dispensable for regulating GC size when GC are elicited in a largely clonal manner, it serves to curb immunodominance under conditions where diverse clonal populations must compete for a constrained niche. Moreover, this is independent of B cell precursor frequency and reflects, at least in part, a B cell-intrinsic role for NUR77. We propose that this is important to preserve early B cell clonal diversity in order to limit holes in the post-immune repertoire and to optimize GC selection.

immunology↗

Gradual development of non-adjacent dependency learning during early childhood

In order to become proficient native speakers, children have to learn the morpho-syntactic relations between distant elements in a sentence, so-called non-adjacent dependencies (NADs). Previous research suggests that NAD learning in children comprises different developmental stages, where until 2 years of age children are able to learn NADs associatively under passive listening conditions, while starting around the age of 3 to 4 years children fail to learn NADs during passive listening. To test whether the transition between these developmental stages occurs gradually, we tested childrens NAD learning in a foreign language using event-related potentials (ERPs). We found ERP evidence of NAD learning across the ages of 1, 2 and 3 years. The amplitude of the ERP effect indexing NAD learning, however, decreased with age. These findings might indicate a gradual transition in childrens ability to learn NADs associatively. Cognitively, this transition might be driven by childrens increasing knowledge of their native language, hindering NAD learning in novel contexts. Neuroanatomically, maturation of the prefrontal cortex might play a crucial role, promoting top-down learning, affecting bottom-up, associative learning. In sum, our study suggests that NAD learning under passive listening conditions undergoes a gradual transition between different developmental stages during early childhood. Research HighlightsO_LITransition between developmental stages of non-adjacent dependency (NAD) learning C_LIO_LIChildren between 1 and 3 years of age showed learning of NADs in a foreign language C_LIO_LIBrain responses revealed associative NAD learning, triggered by passive listening C_LIO_LIGradual decrease of the strength of associative non-adjacent dependency learning C_LI

neuroscience↗

A 3D Reconstruction Algorithm for Real-time Simultaneous Multi-Source EIT Imaging for Lung Function Monitoring

Monitoring regional pulmonary ventilation and pulsatile perfusion changes in a 3D region of interest (ROI) of the lung is a promising application for electrical impedance tomography (EIT). This paper describes a 3D analytical reconstruction algorithm that was embedded in a prototype EIT system to enable a real-time image reconstruction at nearly 20 frames per second for monitoring impedance changes in the chest in real-time. The derivation and results of the 3D analytical forward solution and inverse solution and details of the real-time reconstruction algorithm are given. The algorithm and EIT system are validated with simulated data, in-vitro phantoms, and finally shown to be capable of imaging ventilation and pulsatile perfusion in human subjects. The human subject data was obtained using a high-precision, high-speed and simultaneous multiple current source (SMS-EIT) developed by GE Research. Data was collected using four rows of 8 electrodes for a healthy adult male subject and 2 rows of 16 electrodes for six healthy human female subjects, with one row placed above the breasts and a second row placed at the infra-mammary fold. Each of the female subjects performed a breathing maneuver with a volumetric incentive spirometer, and the volume of air inhaled was calculated from the EIT images. Pulsatile perfusion images were computed from this data, and regional lung filling was also analyzed.

bioengineering↗

Polymer-assisted intratumoral delivery of ethanol: Preclinical investigation of safety and efficacy in a murine breast cancer model

Focal tumor ablation with ethanol could provide benefits in low-resource settings because of its low overall cost, minimal imaging technology requirements, and acceptable clinical outcomes. Unfortunately, ethanol ablation is not commonly utilized because of a lack of predictability of the ablation zone, caused by inefficient retention of ethanol at the injection site. To create a predictable zone of ablation, we have developed a polymer-assisted ablation method using ethyl cellulose (EC) mixed with ethanol. EC is ethanol-soluble and water-insoluble, allowing for EC-ethanol to be injected as a liquid and precipitate into a solid, occluding the leakage of ethanol upon contact with tissue. The aims of this study were to compare the 1) safety, 2) release kinetics, 3) spatial distribution, 4) necrotic volume, and 5) overall survival of EC-ethanol to conventional ethanol ablation in a murine breast tumor model. Non-target tissue damage was monitored through localized adverse events recording, ethanol release kinetics with Raman spectroscopy, injectate distribution with in vivo imaging, target-tissue necrosis with NADH-diaphorase staining, and overall survival by proxy of tumor growth. EC-ethanol exhibited decreased localized adverse events, a slowing of the release rate of ethanol, more compact injection zones, 5-fold increase in target-tissue necrosis, and longer overall survival rates compared to the same volume of pure ethanol. A single 150 {micro}L dose of 6% EC-ethanol achieved a similar survival probability rates to six daily 50 {micro}L doses of pure ethanol used to simulate a slow-release of ethanol over 6 days. Taken together, these results demonstrate that EC-ethanol is safer and more effective than ethanol alone for ablating tumors. Graphical AbstractThe inclusion of ethylcellulose limits extra-tumoral leakage of ethanol and increases the target-tissue ablation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/123125v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@172afb5org.highwire.dtl.DTLVardef@6d96deorg.highwire.dtl.DTLVardef@cbdf9borg.highwire.dtl.DTLVardef@c56187_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗