Biology subjects

Mo, C.

Publications and source records attributed to Mo, C..

12 recordsLinked to original sources

bioRxiv2026

Staphylococcus epidermidis Genomic Plasticity Modulates Horizontal Gene Transfer

Horizontal gene transfer (HGT) is an important driver of evolution, enabling organisms to rapidly adapt to environmental stressors. In bacteria, anti-mobile genetic element (MGE) defense systems are believed to limit HGT, raising the question of how bacterial populations balance defense with the acquisition of genetic novelty. Most insights into anti-MGE defense come from heterologous experimental setups, where candidate systems are artificially expressed in a host and observed over only a few generations. Such approaches can obscure the long-term evolutionary and ecological dynamics of native anti-MGE systems. Here, we show that laboratory-evolved Staphylococcus epidermidis populations rapidly delete a large, flexible genomic region containing anti-MGE defense systems and other accessory genes. This process generates stable, heterogeneous populations composed of cells that either retain or lack these defenses. Loss of this region is associated with a marked increase in HGT. Notably, the balance between anti-MGE defense and HGT is strongly influenced by environmental conditions. In nutrient-rich liquid media, defense systems and adjacent accessory genes are frequently lost, whereas under stress, such as antibiotic exposure, these defenses are maintained, leading to reduced HGT rates. This genetic and phenotypic heterogeneity enhances adaptive potential by enabling the uptake of beneficial MGEs while preserving protection under adverse conditions. Overall, the rapid gain and loss of anti-MGE defense systems highlight how environmental factors, independent of MGEs themselves, can shape HGT dynamics.

microbiology↗

bioRxiv2025

Cyclin-dependent kinase 9 inhibitors as oncogene signaling modulators in combination with targeted therapy for the treatment of colorectal cancer

BackgroundColorectal cancer (CRC) is the second deadliest cancer worldwide and new treatment options are urgently needed. Cyclin dependent kinase 9 (CDK9) promotes aberrant RNA transcription in cancer and is a promising target for cancer therapies. MethodsUsing CRC cell lines as well as newly established patient-derived organoid models of CRC, we studied the clinically promising CDK9 inhibitors (AZD4573, BAY1125152/VIP152/enitociclib, and NVP2) to determine their therapeutic potential. We investigated the efficacy and mechanisms of action through cell growth and cytotoxicity assays, RNAseq, immunoblotting, and IHC. ResultsWe found CDK9 inhibitors to be highly potent against CRC, through suppression of proliferation and induction of apoptosis. Our results demonstrated CDK9 inhibitors to be broadly active against a set of CRC models derived from a diverse patient population. Our mechanistic studies showed significant suppression of the Mitogen-active protein kinase (MAPK) signaling pathway due to CDK9 inhibitor treatment, suggesting that CDK9 inhibitor efficacy could be enhanced when combined with MAPK pathway inhibitors. As proof-of-concept, we found that CDK9 inhibitors and MEK inhibitors could be combined to synergistically suppress CRC growth and survival. ConclusionsCDK9 inhibitors show promising activity against patient-derived models of CRC. MAPK signaling is particularly suppressed by CDK9 inhibitors. Combining CDK9 inhibitors and targeted therapy against MAPK signaling pathway may be a viable strategy worthy of further investigation preclinically and clinically. State of translational relevanceNovel therapies for chemotherapy-refractory CRC remain urgently needed. Rapid validation of efficacy in appropriate translational models can provide the necessary rationale to test new therapies in clinical trials. Using newly established patient-derived organoids, we validate the preclinical efficacy of transcriptional CDK9 inhibitors against CRC. This is a therapeutic class that has been scarcely evaluated for efficacy against CRC. We found that CDK9 inhibitors potently inhibit patient-derived organoid models of CRC. Our mechanistic work also reveals that clinically achievable concentrations of CDK9 inhibitor treatment results in suppression of MAPK signaling. As proof-of-concept of the potential actionability of our findings, we demonstrate that CDK9 inhibitors can be combined with MEK inhibitors to synergistically suppress CRC growth. Our study provides new patient-derived CRC models as a resource available to others for therapeutic testing, as well as a roadmap for novel hypotheses about synergistic combination treatments using CDK9 inhibitors.

cancer biology↗

bioRxiv2025

Disruption of transthalamic circuitry from primary visual cortex impairs visual discrimination in mice

Layer 5 (L5) of the cortex provides strong driving input to higher-order thalamic nuclei, such as the pulvinar in the visual system, forming the basis of cortico-thalamo-cortical (transthalamic) circuits. These circuits provide a communication route between cortical areas in parallel to direct corticocortical connections, but their specific role in perception and behavior remains unclear. Using targeted optogenetic inhibition in mice performing a visual discrimination task, we selectively suppressed the corticothalamic input from L5 cells in primary visual cortex (V1) at their terminals in pulvinar. This suppresses transthalamic circuits from V1; furthermore, any effect on direct corticocortical projections and local V1 circuitry would thus result from transthalamic inputs (e.g., V1 to pulvinar back to V1 (Miller-Hansen and Sherman, 2022). Such suppression of transthalamic processing during visual stimulus presentation of drifting gratings significantly impaired discrimination performance across different orientations. The impact on behavior was specific to the portion of visual space that retinotopically coincided with the V1 L5 corticothalamic inhibition. These results highlight the importance of incorporating L5-initiated transthalamic circuits into cortical processing frameworks, particularly those addressing how the hierarchical propagation of sensory signals supports perceptual decision-making. SIGNIFICANCE STATEMENTAppreciation of pathways for transthalamic communication between cortical areas, organized in parallel with direct connections, has transformed our thinking about cortical functioning writ large. Studies of transthalamic pathways initially concentrated on their anatomy and physiology, but there has been a shift towards understanding their importance to cognitive behavior. Here, we have used an optogenetic approach in mice to selectively inhibit the transthalamic pathway from primary visual cortex to other cortical areas and back to itself. We find that such inhibition degrades the animals ability to discriminate, showing for the first time that specific inhibition of visual transthalamic circuitry reduces visual discrimination. This causal data adds to the growing evidence for the importance of transthalamic signaling in perceptual processing.

neuroscience↗

bioRxiv2024

Spatial frequency channels mediate a visual metric for human spatial perception

An intriguing mystery concerning spatial vision is that the perceived spatial property information of the same stimulus varies in different contexts. While previous findings are suggestive of an adaptable mental ruler by which the raw retinal signals are flexibly scaled according to the prevailing context, whether and how such a putative mental ruler is utilized by the visual brain remain largely unknown. We hypothesized that the putative mental ruler was represented by multiple differently-tuned spatial frequency (SF) channels. A finer division of the ruler, signaled by dominance of the high-SF channels, is translated to a wider-spread topography of neural activation via concentration of neuronal receptive fields, causing perceptual inflation. Combining psychophysics and fMRI, we found that modulation of SF channels caused a systematic distortion in perceived separation, a representative fundamental spatial property, and a global displacement of population receptive fields (pRF) in primary visual cortex. Computational modeling further showed that both the perceptual distortion and the global pRF displacement were functionally coupled with the magnitude of SF channel modulation. Our findings reveal, for the first time, an adjustable mental ruler that commonly governs the perception of spatial property information in different contexts, and suggest a cognitive scaling system based on SF channel reweighting and displacement of neuronal RFs.

neuroscience↗

bioRxiv2024

Deep mutational scanning identifies variants of Cas1 and Cas2 that increase spacer acquisition in type II-A CRISPR-Cas systems

A remarkable feature of CRISPR-Cas systems is their ability to acquire short sequences from invading viruses to create a molecular record of infection. These sequences, known as spacers, are inserted into the CRISPR locus by the Cas1-Cas2 integrase complex and mediate sequence- specific immunity in prokaryotes. Spacer acquisition has been used to develop unique biotechnological applications such as the immunization of industrially relevant bacteria against bacteriophage infection and the recording of biological signals into stable genetic information. These technologies, however, are constrained by the low efficiency of the spacer acquisition process. To overcome this limitation, we developed a genetic system that combined deep mutational scanning (DMS) of cas genes from the Streptococcus pyogenes type II-A CRISPR- Cas system with a method that selects bacteria that acquire new spacers. This procedure enabled the identification of cas mutations that support up to a sevenfold increase in the levels of spacer acquisition and a significant enhancement of immunity against phage infection. In addition, our analysis revealed key interactions at the Cas1-Cas2 interface critical for spacer integration. Our findings provide insights into the molecular determinants of spacer acquisition and offer a platform to improve CRISPR-Cas-based applications.

microbiology↗

bioRxiv2024

Bacteriophage infection drives loss of β-lactam resistance in methicillin-resistant Staphylococcus aureus

Bacteriophage (phage) therapy is a promising means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical relevance. Here we report the discovery that infection by certain staphylococcal phages sensitizes different strains of methicillin-resistant Staphylococcus aureus (MRSA) to {beta}-lactams, a class of antibiotics against which MRSA is typically resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different {beta}-lactams compared to uninfected bacteria. Transcriptomic profiling reveals that these evolved MRSA strains possess highly modulated transcriptional profiles, where numerous genes involved in S. aureus virulence were downregulated. Phage-treated MRSA exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Despite sharing similar phenotypes, whole-sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.

microbiology↗

bioRxiv2023

A transthalamic pathway is crucial for stimulus feature selectivity in higher order cortex

Perception arises from activity between cortical areas, first primary cortex and then higher order cortices. This communication is served in part by transthalamic (cortico-thalamo-cortical) pathways, which ubiquitously parallel direct corticocortical pathways, but their role in sensory processing has largely remained unexplored. Here, we show that the transthalamic pathway linking somatosensory cortices propagates task-relevant information required for correct sensory decisions. Using optogenetics, we specifically inhibited the pathway at its synapse in higher order somatosensory thalamus of mice performing a texture-based discrimination task. We concurrently monitored the cellular effects of inhibition in primary or secondary cortex using two-photon calcium imaging. Inhibition severely impaired performance despite intact direct corticocortical projections, thus challenging the purely corticocentric map of perception. Interestingly, the inhibition did not reduce overall cell responsiveness to texture stimulation in somatosensory cortex, but rather disrupted the texture selectivity of cells, a discriminability that develops over task learning. This discriminability was more disrupted in the secondary than primary somatosensory cortex, emphasizing the feedforward influence of the transthalamic route. Transthalamic pathways thus appear critical in delivering performance-relevant information to higher order cortex and are critical hierarchical pathways in perceptual decision-making.

neuroscience↗

bioRxiv2021

A new Mendelian Randomization method to estimate causal effects of multivariable brain imaging exposures

The advent of simultaneously collected imaging-genetics data in large study cohorts provides an unprecedented opportunity to assess the causal effect of brain imaging traits on externally measured experimental results (e.g., cognitive tests) by treating genetic variants as instrumental variables. However, classic Mendelian Randomization methods are limited when handling high-throughput imaging traits as exposures to identify causal effects. We propose a new Mendelian Randomization framework to jointly select instrumental variables and imaging exposures, and then estimate the causal effect of multivariable imaging data on the outcome. We validate the proposed method with extensive data analyses and compare it with existing methods. We further apply our method to evaluate the causal effect of white matter microstructure integrity on cognitive function. The findings suggest that our method achieved better performance regarding sensitivity, bias, and false discovery rate compared to individually assessing the causal effect of a single exposure and jointly assessing the causal effect of multiple exposures without dimension reduction. Our application results indicated that WM measures across different tracts have a joint causal effect that significantly impacts the cognitive function among the participants from the UK Biobank.

bioinformatics↗

bioRxiv2021

Numb is required for optimal contraction of skeletal muscle

BackgroundThe role of Numb, a protein that is important for cell fate and development was investigated in adult skeletal muscle in mice using a conditional, inducible knockout (cKO) model. MethodsNumb expression was evaluated by Western blot. Numb localization was determined by confocal microscopy. The effects of cKO of Numb and the closely-related gene Numb-like in skeletal muscle fibers was evaluated by in-situ physiology; transmission and focused ion beam scanning electron microscopy; 3-dimensional reconstruction of mitochondrial; lipidomics; and bulk RNA-sequencing. Additional studies using primary mouse myotubes investigated the effects the effects of Numb knockdown on cell fusion, mitochondrial function and calcium transients. ResultsNumb protein expression was reduced by [~]70% (p < 0.01) at 24 as compared to 3 months of age. Numb was localized within muscle fibers as bands traversing fibers at regularly spaced intervals in close proximity to dihydropyridine receptors. The cKO of Numb and Numb-like reduced specific tetanic force by 36%, p < 0.01), altered mitochondrial spatial relationships to sarcomeric structures, increased Z-line spacing by 30% (p < 0.0001), perturbed sarcoplasmic reticulum organization and reduced mitochondrial volume by over 80% (p < 0.01). Only six genes were differentially expressed in cKO mice: Itga4, Sema7a, Irgm2, Vezf1, Mib1 and Tmem132a. Several lipid mediators derived from polyunsaturated fatty acid (PUFAs) through lipoxygenases were upregulated in Numb cKO skeletal muscle; 12-HEPE was increased by [~]250% (p < 0.05) and 17,18-EpETE by [~]240% (p < 0.05). In mouse primary myotubes, Numb knock-down reduced cell fusion ([~]20%, p < 0.01) and mitochondrial function and delayed the caffeine-induced rise in cytosolic calcium concentrations by more than 100% (p < 0.01). ConclusionsThese findings implicate Numb as a critical factor in skeletal muscle structure and function which appear to be critical for calcium release; we therefore speculate Numb plays critical roles in excitation-contraction coupling, one of the putative targets of aged skeletal muscles. These findings provide new insights into the molecular underpinnings of the loss of muscle function observed with sarcopenia.

physiology↗

bioRxiv2020

White matter integrity and nicotine dependence in smokers: evaluating vertical and horizontal pleiotropy

Smoking is a heritable behavior and nicotine dependency is complex mechanism supported by both positive and negative reinforcements. We hypothesized that cerebral white matter (WM) may mediate the individual dependency on nicotine integrity because its integrity is altered in smokers and shows dose-related response to nicotine administration. Two vertical and one horizontal pleiotropy pathways that combined individual genetic variations, measure of WM integrity by fractional anisotropy (FA), and nicotine dependence were evaluated in a large epidemiological sample (N=12,264 and 4,654 participants that have genetic, FA measure and nicotine dependence data available for smoking status and cigarettes per day (CPD), respectively) collected UK Biobank. We started by selecting the candidate genetic regions including genetic risk factors associated with smoking from genome-wide association study (GWAS) for causal pathway analysis. Then we identified pleiotropic loci that influence both nicotine dependence and WM integrity from these regions. We tested a horizontal pleiotropy pathway: (A) genetic risk factors associated with smoking were independently affecting both nicotine dependence and WM integrity. We also evaluated two vertical pleiotropy that assumed that individual genetic factors associated with nicotine dependence impacted B) impacted WM integrity which in turn led to higher nicotine dependence vs. C) led to nicotine dependence and resulting white matter alterations. There were 10 and 23 candidate pleiotropic variants identified for smoking status and CPD traits. All these variants exhibited vertical pleiotropy. For smoking status, the genetic effect on smoking status was mediated by FA measures over multiple brain regions. The variants were located in a gene SARDH, which catalyzes the oxidative demethylation of sarcosine that plays a role in reducing tolerance effect on nicotine. Conversely, CPD was a significant mediator in the vertical pleiotropy pathway to FA. The identified variants were located in gene IREB2, that was reported as a susceptibility gene for both neurodegeneration and smoking-induced diseases.

neuroscience↗

bioRxiv2020

Genetic Fine-mapping with Dense Linkage Disequilibrium Blocks: genetics of nicotine dependence

Fine-mapping is an analytical step to perform causal prioritization of the polymorphic variants on a trait-associated genomic region observed from genome-wide association studies (GWAS). The prioritization of causal variants can be challenging due to the linkage disequilibrium (LD) patterns among hundreds to thousands of polymorphisms associated with a trait. We propose a novel{ell} 0 graph norm shrinkage algorithm to select causal variants from dense LD blocks consisting of highly correlated SNPs that may not be proximal or contiguous. We extract dense LD blocks and perform regression shrinkage to calculate a prioritization score to select a parsimonious set of causal variants. Our approach is computationally efficient and allows performing fine-mapping on thousands of polymorphisms. We demonstrate its application using a large UK Biobank (UKBB) sample related to nicotine addiction. Our results suggest that polymorphic variances in both neighboring and distant variants can be consolidated into dense blocks of highly correlated loci. Simulations were used to evaluate and compare the performance of our method and existing fine-mapping algorithms. The results demonstrated that our method outperformed comparable fine-mapping methods with increased sensitivity and reduced false-positive error rate regarding causal variant selection. The application of this method to smoking severity trait in UKBB sample replicated previously reported loci and suggested the causal prioritization of genetic effects on nicotine dependency. Author summaryDisentangling the complex linkage disequilibrium (LD) pattern and selecting the underlying causal variants have been a long-term challenge for genetic fine-mapping. We find that the LD pattern within GWAS loci is intrinsically organized in delicate graph topological structures, which can be effectively learned by our novel{ell} 0 graph norm shrinkage algorithm. The extracted LD graph structure is critical for causal variant selection. Moreover, our method is less constrained by the width of GWAS loci and thus can fine-map a massive number of correlated SNPs.

genetics↗

bioRxiv2019

The role of swnR gene on the biosynthesis pathway of the swainsonine in Metarhizium anisopliae

Swainsonine (SW) is the principal toxic ingredient of locoweeds, and is produced by fungi including Metarhizium anisopliae, Slafractonia leguminicola, and Alternaria oxytropis. Studies of the SW biosynthesis pathway in these fungi have demonstrated the requirement for a swnK gene and the presence of a variety of other SWN cluster genes, but have not determined a precise role for the swnR gene, which encodes a NADB Rossmann-fold reductase, nor if it is necessary for the biosynthesis of SW. In this study, we used homologous recombination (HR) to knock out the swnR gene of M. anisopliae to determine its effect on the SW biosynthesis pathway. The concentration of SW was measured in the fermentation broth of M. anisopliae at 1 d, 3 d, 5 d and 7 d using a Q Exactive Mass Spectrometer. The gene for swnR was detected by RT-qPCR. To determine the role of the swnR gene in the SW biosynthesis pathway of M. anisopliae, we used PEG-mediated homologous recombination (HR) to transform a wild-type strain (WT) with a Benomyl (ben)-resistant fragment to knock out the swnR gene producing a mutant-type strain (MT). A complemented-type (CT) strain was produced by adding a complementation vector that contains the glufosinate (herbicide) resistance (bar) gene as a marker. The content of SW decreased, but was not eliminated in the fermentation broth of the MT strain, and returned to the original level in the CT strain. These results indicate that the swnR gene plays a crucial role in the SW biosynthesis pathway of M. anisopliae, but suggests that another gene in the fungus may share the function of swnR.

molecular biology↗