Biology subjects

Cannon, D.

Publications and source records attributed to Cannon, D..

6 recordsLinked to original sources

bioRxiv2025

Homeostatic regulation of a motor circuit through temperature sensing rather than activity sensing

Homeostasis is a driving principle in physiology. To achieve homeostatic control of neural activity, neurons monitor their activity levels and then initiate corrective adjustments in excitability when activity strays from a set point. However, fluctuations in the brain microenvironment, such as temperature, pH, and other ions represent some of the most common perturbations to neural function in animals. Therefore, it is unclear if activity sensing is a universal strategy for different types of perturbations or if stability may arise by sensing specific environmental cues. Here we show the respiratory network of amphibians mounts a fast homeostatic response to restore motor function following inactivity caused by cooling over the physiological range. This response was not initiated by inactivity, but rather, by temperature. Compensation involved cold-activation of the noradrenergic system via mechanisms that involve inhibition of the Na+/K+ ATPase, causing {beta}-adrenoceptor signaling that enhanced network excitability. Thus, acute cooling initiates a modulatory response that opposes inactivity and enhances network excitability. As the nervous system of all animals is subjected to changes in the microenvironment, some circuits may have selected regulatory systems tuned to environmental variables in place of, or in addition to, activity-dependent control mechanisms. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/632419v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@15d8cf5org.highwire.dtl.DTLVardef@d16920org.highwire.dtl.DTLVardef@4cb865org.highwire.dtl.DTLVardef@de266f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

CytoCellDB: A Resource Database For Classification and Analysis of Extrachromosomal DNA in Cancer

Extrachromosomal DNA (ecDNA), or double minute chromosomes, are established cytogenetic markers for malignancy and genome instability. More recently, the cancer community has gained a heightened awareness of the roles of ecDNA in cancer proliferation, drug resistance and epigenetic remodeling. A current hindrance to understanding the biological roles of ecDNA is the lack of available cell line model systems with experimental cytogenetic data that confirm ecDNA status. Although several recent landmark studies have identified common cell lines and tumor models with ecDNA, the current sample size limits our ability to detect ecDNA-driven molecular differences due to limitations in power. Increasing the number of model systems known to express ecDNA would provide new avenues for understanding the fundamental underpinnings of ecDNA biology and would unlock a wealth of potential targeting strategies for ecDNA-driven cancers. To bridge this gap, we created CytoCellDB, a resource that provides karyotype annotations and leverages publicly available global cell line data from the Cancer Dependency Map (DepMap) and the Cancer Cell Line Encyclopedia (CCLE). Here, we identify 139 cell lines that express ecDNA, which is a 200% increase from the current sample size. We expanded the total number of cancer cell lines with ecDNA annotations to 577, which is a 400% increase or 31% of cell lines in CCLE/ DepMap. We demonstrate that a strength of CytoCellDB is the ability to interrogate ecDNA, and a compendium of other chromosomal aberrations, in the context of cancer-specific vulnerabilities, drug sensitivities, and molecular data (genomics, transcriptomics, methylation, proteomics). We anticipate that CytoCellDB will advance cytogenomics research and population-scale discoveries related to ecDNA as well as provide insights into strategies and best practices for determining novel therapeutics that overcome ecDNA-driven drug resistance.

genomics↗

bioRxiv2020

In vitro Evolution of Antibody Affinity via Insertional Mutagenesis Scanning of an Entire Antibody Variable Region

We report the first systematic combinatorial exploration of affinity enhancement of antibodies by insertions and deletions (InDels). Transposon-based introduction of InDels via the method TRIAD was used to generate large libraries with random in-frame InDels across the entire scFv gene that were further recombined and screened by ribosome display. Knowledge of potential insertion points from TRIAD libraries formed the basis of exploration of length and sequence diversity of novel insertions by insertional-scanning mutagenesis (ISM). An overall 256-fold affinity improvement of an anti-IL-13 antibody BAK1 as a result of InDel mutagenesis and combination with known point mutations validates this approach and suggests that the results of this InDel approach and conventional exploration of point mutations can synergize to generate antibodies with higher affinity. SignificanceInsertion/deletion (InDel) mutations play key roles in genome and protein evolution. Despite their prominence in evolutionary history, the potential of InDels for changing function in protein engineering by directed evolution remains unexplored. Instead point mutagenesis is widely used. Here we create antibody libraries containing InDels and demonstrate that affinity maturation can be achieved in this way, establishing an alternative to the point mutation strategies employed in all previous in vitro selections. These InDels mirror the observation of considerable length variation in loops of natural antibodies originating from the same germline genes and be combined with point mutations, making both natural sources of functional innovation available for artificial evolution in the test tube.

biochemistry↗

bioRxiv2020

Validation of a SARS-CoV-2 spike ELISA for use in contact investigations and serosurveillance

Since emergence of SARS-CoV-2 in late 2019, there has been a critical need to understand prevalence, transmission patterns, to calculate the burden of disease and case fatality rates. Molecular diagnostics, the gold standard for identifying viremic cases, are not ideal for determining true case counts and rates of asymptomatic infection. Serological detection of SARS-CoV-2 specific antibodies can contribute to filling these knowledge gaps. In this study, we describe optimization and validation of a SARS-CoV-2-specific-enzyme linked immunosorbent assay (ELISA) using the prefusion-stabilized form of the spike protein [1]. We performed receiver operator characteristic (ROC) analyses to define the specificities and sensitivities of the optimized assay and examined cross reactivity with immune sera from persons confirmed to have had infections with other coronaviruses. These assays will be used to perform contact investigations and to conduct large-scale, cross sectional surveillance to define disease burden in the population.

immunology↗

bioRxiv2020

Greater male than female variability in regional brain structure across the lifespan

For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

neuroscience↗

bioRxiv2019

10Kin1day: A bottom-up neuroimaging initiative

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

neuroscience↗